JP2007509943A - Nucleoside compounds for the treatment of viral infections - Google Patents

Abstract

  Disclosed are compounds, compositions and methods for treating viral infections caused by Flaviviridae viruses such as hepatitis C virus.

Description

FIELD OF THE INVENTION This invention relates to a method for preparing specific compounds for treating mammalian viral infections mediated, at least in part, by viruses of the Flaviviridae family. The present invention is also directed to novel intermediates used in these methods.

This application is a continuation-in-part of U.S. patent applications 10 / 861,090, 10 / 861,311, and 10 / 861,219, all filed June 4, 2004, each of which is a Claims the benefit under 35 USC § 119 (e) of US Provisional Application No. 60 / 515,153, filed 27 October 2003. This application also claims the benefit under 35 USC § 119 (e) of US provisional application 60 / 602,815 filed 18 August 2004. All of the aforementioned applications are incorporated herein by reference in their entirety.

Cited references The following publications are cited in this application in superscript.
1. Giangaspero, et al., Arch. Virol. Suppl., 7: 53-62 (1993)
2. Giangaspero, et al., Int. J. STD. AIDS, 4 (5): 300-302 (1993)
3. Yolken, et al., Lancet, 1 (8637): 517-20 (1989)
4. Wilks, et al., Lancet, 1 (8629): 107 (1989)
5. Giangaspero, et al., Lancet, 2: 110 (1988)
6. Potts, et al., Lancet, 1 (8539): 972-973 (1987)
7. Cornberg, et al., "Hepatitis C: therapeutic perspectives." Forum (Genova), 11 (2): 154-62 (2001)
8. Dymock, et al., Antivir. Chem. Chemother. 11 (2): 79-96 (2000)
9. Devos, et al., International Application No. 02/18404 A2, published March 7, 2002
10. Sommadossi, et al., International Application No. 01/90121, published 23 May, 2001
11. Carroll, SS, et al., International Application No. 02057287 published July 25, 2002
12. Carroll, SS, et al., International Application No. 02057425, published July 25, 2002
13. Roberts, et al., US patent application Ser. No. 10 / 861,090, filed Jun. 4, 2004
14. Roberts, et al., U.S. Patent Application No. 10 / 861,311 filed June 4, 2004

  All of the aforementioned publications and applications are hereby incorporated by reference in their entirety as if each individual publication or application was specifically and individually indicated to be incorporated herein by reference in its entirety. Be incorporated.

State-of-the-art Flaviviridae viruses consist of three genera: pestiviruses, flaviviruses, and hepaciviruses (hepatitis C virus). Of these genera, flaviviruses and hepaciviruses are representative of important human pathogens and are widespread throughout the world. There are 38 flaviviruses associated with human disease, including dengue virus, yellow fever virus and Japanese encephalitis virus. Flavivirus causes a series of acute febrile diseases as well as encephalitic and hemorrhagic diseases. Hepacivirus currently infects about 2-3% of the world's population, causing persistent infections that lead to chronic liver disease, cirrhosis, hepatocellular carcinoma, and liver dysfunction. Human pestiviruses are not as well characterized as animal pestiviruses. However, serological studies have shown considerable pestivirus exposure in humans. Human pestivirus infections have been implicated in several diseases including, but not limited to, congenital brain injury, infant gastroenteritis, and chronic diarrhea in human immunodeficiency virus (HIV) positive patients. and are ^1-6.

  Currently, there are no antiviral drugs for preventing or treating pestivirus or flavivirus infections. For hepacivirus, or hepatitis C virus (HCV) infection, interferon alpha (IFN) is the only drug currently approved in the United States. HCV is the main pathogen of post-transfusion and sporadic non-A non-B hepatitis. Infection with HCV is insidious in a high proportion of chronically infected (and infectious) carriers and may not experience clinical symptoms for many years.

  Currently, the only acceptable treatment for chronic HCV is interferon (IFN-α), which requires at least 6 months of treatment and / or ribavirin, inhibits viral replication in infected cells, and at the same time in some patients It can also improve liver function.

  IFN-α has characteristic biological effects such as antiviral, immunomodulatory, and antitumor activity that are produced and secreted by most animal nucleated cells in response to several diseases, especially viral infections It belongs to the natural small protein family. IFN-α is an important regulator of growth and differentiation that affects cell communication and immune regulation. However, HCV treatment with interferon has a limited long-term effect with a response rate of about 25%. In addition, treatment of HCV with interferon has adverse side effects such as fatigue, fever, chills, headache, muscle pain, joint pain, mild hair loss, mental effects and related disorders, autoimmune phenomena and related disorders, and thyroid dysfunction Was often accompanied.

  Ribavirin (1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide), an inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH), has been successfully used in the treatment of HCV. To increase the efficacy of Despite the introduction of ribavirin, more than 50% of patients do not clear the virus with current standard therapies for interferon-α (IFN) and ribavirin. To date, the standard treatment for chronic hepatitis C has been changed to a combination of PEG-IFN and ribavirin. However, some patients still have significant side effects primarily related to ribavirin. Ribavirin causes significant hemolysis in 10-20% of patients treated with current recommended doses, and exhibits both teratogenic and fetal toxicity.

Other approaches have been taken to fight viruses. This includes, for example, the application of antisense oligonucleotides or ribozymes to inhibit HCV replication. In addition, low molecular weight compounds that directly inhibit HCV proteins and prevent viral replication are considered attractive strategies for controlling HCV infection. NS3 / 4A serine protease, ribonucleic acid (RNA) helicase, and RNA-dependent RNA polymerase may be potential targets for new ^drugs7,8 .

Devos et al. ⁹ describe purine and pyrimidine nucleoside derivatives and their use as inhibitors of HCV RNA replication. Sommadossi et al. ¹⁰ describe 1 ′, 2 ′ or 3′-modified nucleosides and their use to treat HCV infected hosts. Carroll et al. ^11,12 describe nucleosides as inhibitors of RNA-dependent RNA viral polymerase.

Recently, Roberts et al. ^13,14 have reported specific 7- (2′-substituted-β-D-ribofuranosyl) -4-amino-5- (optionally substituted ethyn-1-yl) -pyrrolo [2, It has been disclosed that 3-d] pyrimidine compounds have potent activity against HCV. These references are incorporated herein by reference in their entirety.

（式中
Yは結合、-CH₂-または-O-からなる群より選択され；
W、W¹およびW²はそれぞれ水素および薬学的に許容されるプロドラッグからなる群より独立に選択され；かつ
Tは下記からなる群より選択される
a）-C≡C-R（Rは下記からなる群より選択される
i）トリ(C₁〜C₄)アルキルシリル、-C(O)NR¹R²、アルコキシアルキル、ヘテロアリール、置換ヘテロアリール、フェニル、ならびにアルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、アルコキシ、置換アルコキシ、アシル、アシルアミノ、アシルオキシ、アミノアシル、アミジノ、アミノ、置換アミノ、カルボキシル、カルボキシルエステル、シアノ、シクロアルキル、置換シクロアルキル、シクロアルコキシ、置換シクロアルコキシ、グアニジノ、ハロ、ヘテロアリール、置換ヘテロアリール、ヒドラジノ、ヒドロキシル、ニトロ、チオール、および-S(O)_mR³からなる群より選択される1から3個の置換基で置換されたフェニル；
ただしR¹およびR²は、R¹およびR²の一つだけがアミノまたは置換アミノであるとの条件で、水素、アルキル、置換アルキル、アミノ、置換アミノ、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環および置換複素環からなる群より独立に選択され、さらにR¹およびR²はそれらに結合している窒素原子と一緒に複素環または置換複素環を形成し；
R³はアルキル、置換アルキル、アミノ、置換アミノ、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環および置換複素環からなる群より選択され；かつ
mは0、1または2の整数である；
ii）-C(O)OR¹⁴（R¹⁴は水素、アルキルまたは置換アルキルである））；
b）-CH=CH-Q²（Q²は水素またはcis-アルコキシから選択される）；
c）-C(O)H；
d）-CH=NNHR¹⁵（R¹⁵はHまたはアルキルである）；
e）-CH=N(OR¹⁵)（R¹⁵は前述の定義のとおりである）；
f）-CH(OR¹⁶)₂（R¹⁶は(C₃〜C₆)アルキルである）；および
g）-B(OR¹⁵)₂（R¹⁵は前述のとおりである））；
およびその薬学的に許容される塩または部分塩を目的とする。 SUMMARY OF THE INVENTION The present invention is directed to novel compounds that are useful, at least in part, in the treatment of mammalian viral infections mediated by Flaviviridae viruses. In particular, the present invention provides compounds of formula I

(In the formula
Y is selected from the group consisting of a bond, —CH ₂ — or —O—;
W, W ¹ and W ² are each independently selected from the group consisting of hydrogen and a pharmaceutically acceptable prodrug; and
T is selected from the group consisting of
a) -C≡CR (R is selected from the group consisting of
i) tri (C ₁ ~C ₄₎ ^{alkylsilyl, -C (O) NR 1 R} 2, alkoxyalkyl, heteroaryl, substituted heteroaryl, phenyl, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl , Alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, aminoacyl, amidino, amino, substituted amino, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, guanidino, halo, heteroaryl, substituted Phenyl substituted with 1 to 3 substituents selected from the group consisting of heteroaryl, hydrazino, hydroxyl, nitro, thiol, and —S (O) _m R ³ ;
Where R ¹ and R ² are hydrogen, alkyl, substituted alkyl, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted, provided that only one of R ¹ and R ² is amino or substituted amino Independently selected from the group consisting of heteroaryl, heterocycle and substituted heterocycle, and R ¹ and R ² together with the nitrogen atom bonded to them form a heterocycle or substituted heterocycle;
R ³ is selected from the group consisting of alkyl, substituted alkyl, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle;
m is an integer of 0, 1 or 2;
ii) -C (O) OR ¹⁴ (R ¹⁴ is hydrogen, alkyl or substituted alkyl));
b) -CH = CH-Q ² (Q ² is selected from hydrogen or cis-alkoxy);
c) -C (O) H;
d) -CH = NNHR ¹⁵ (R ¹⁵ is H or alkyl);
e) —CH═N (OR ¹⁵ ) (R ¹⁵ is as defined above);
f) —CH (OR ¹⁶ ) ₂ (R ¹⁶ is (C ₃ -C ₆ ) alkyl); and
g) -B (OR ¹⁵ ) ₂ (R ¹⁵ is as described above));
And pharmaceutically acceptable salts or partial salts thereof.

In one preferred embodiment, T is -C≡CR, and R is tri (C ₁ ~C ₄₎ ^{alkylsilyl, -C (O) NR 1 R} 2, alkoxyalkyl, heteroaryl, substituted heteroaryl, phenyl , As well as alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, aminoacyl, amidino, amino, substituted amino, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl 1 to 3 substituents selected from the group consisting of, cycloalkoxy, substituted cycloalkoxy, guanidino, halo, heteroaryl, substituted heteroaryl, hydrazino, hydroxyl, nitro, thiol, and —S (O) _m R ³ Selected from the group consisting of phenyl substituted with
Where R ¹ and R ² are hydrogen, alkyl, substituted alkyl, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted, provided that only one of R ¹ and R ² is amino or substituted amino Independently selected from the group consisting of heteroaryl, heterocycle and substituted heterocycle, and R ¹ and R ² together with the nitrogen atom bonded to them form a heterocycle or substituted heterocycle;
R ³ is selected from the group consisting of alkyl, substituted alkyl, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle;
m is an integer of 0, 1 or 2;
Or a pharmaceutically acceptable salt thereof.
Select More preferably, R is _{phenyl, -C (O) NH 2,} -Si (CH 3) 3, pyrid-2-yl, 4-methoxyphenyl, and from the group consisting of -CH (OCH ₂ CH _{3) 2} Is done.

  In another preferred embodiment, T is —C≡C—R and R is —C (O) OH.

In another preferred embodiment, T is —C≡CR, R is —C (O) OR ¹⁴ , and R ¹⁴ is alkyl.

In another preferred embodiment, T is —CH═CH—Q ² (Q ² is selected from hydrogen or cis-methoxy).

  In another preferred embodiment, T is —C (═O) H.

In another preferred embodiment, T is —CH═NNHR ¹⁵ (R ¹⁵ is independently selected from the group consisting of hydrogen and alkyl).

In another preferred embodiment, T is —CH═N (OR ¹⁵ ) (R ¹⁵ is independently selected from the group consisting of hydrogen and alkyl).

In another preferred embodiment, T is —CH (OR ¹⁶ ) ₂ (R ¹⁶ is independently (C ₃ -C ₆ ) alkyl).

In another preferred embodiment, T is —B (OR ¹⁵ ) ₂ (R ¹⁵ is independently selected from the group consisting of hydrogen and alkyl).

In another preferred embodiment, W, W ¹ and W ² are each independently hydrogen or acyl, oxyacyl, phosphonate, phosphate ester, phosphate, phosphonamidate, phosphorodiamidate, phosphoramidate monoester , Cyclic phosphoramidates, cyclic phosphorodiamidates, phosphoramidate diesters, and —C (O) CHR ³⁰ NH _{2, where} R ³⁰ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl A pharmaceutically acceptable prodrug selected from the group consisting of: Preferably, R ³⁰ is from an amino acid side chain, more preferably from an L-amino acid.

Preferably W is H or W ¹ is H or W ² is H. More preferably, W and W ¹ are H, W and W ² are H, or W ¹ and W ² are H. Even more preferably, W, W ¹ and W ² are H.

In yet another preferred embodiment, W ¹ and W ² is hydrogen and W is hydrogen or acyl, oxyacyl, phosphonate, phosphate esters, phosphate, phosphonamidate, phosphorodiamidate, Hosuhorami Dating monoester, cyclic phosphoramidate, a pharmaceutically acceptable prodrug selected from the group consisting of cyclic phosphorodiamidate, phosphoramidate diester, and _{^{-C (O) CHR 30 NH 2}} ,.

（式中、R³⁰は前述の定義のとおりであり、R⁸は水素またはアルキルであり、かつR¹⁰はアルキル、置換アルキル、アリール、置換アリール、シクロアルキル、置換シクロアルキル、ヘテロアリール、置換ヘテロアリール、複素環および置換複素環からなる群より選択される）で表される。好ましい態様において、R³⁰はL-アミノ酸由来である。 In one particularly preferred embodiment, W ¹ and W ² are hydrogen and W is of the following formula:

Wherein R ³⁰ is as defined above, R ⁸ is hydrogen or alkyl, and R ¹⁰ is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted hetero Selected from the group consisting of aryl, heterocycle and substituted heterocycle). In a preferred embodiment, R ³⁰ is derived from an L-amino acid.

（式中、R³⁰は前述の定義のとおりである）で表される。前述と同じく、R³⁰は好ましくはL-アミノ酸由来である。 In another particularly preferred embodiment, W and W ² are hydrogen and W ¹ is of the formula:

(Wherein R ³⁰ is as defined above). As before, R ³⁰ is preferably derived from an L-amino acid.

  The compounds of the present invention are either active as antiviral agents or are useful as intermediates in the viral agent preparation described herein.

  The present invention is also directed to a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound described herein or a mixture of one or more such compounds. .

  The invention further relates to a method of treating a viral infection mediated by a virus of the Flaviviridae family, such as HCV, in a mammal, wherein the viral infection is diagnosed or is a viral infection. A pharmaceutical comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound described herein or a mixture of one or more such compounds in a mammal at high risk of developing Also contemplated is a method comprising administering a composition.

  In yet another embodiment of the invention, a method of treating or preventing a viral infection in a mammal, wherein the compound of the invention is administered in a therapeutically effective amount of one or more agents active against HCV. And methods of administration in combination. Active agents against HCV include ribavirin, levovirin, viramidine, inhibitors of thymosin alpha-1, NS3 serine protease, and inhibitors of inosine monophosphate dehydrogenase, interferon-alpha, alone or in combination with ribavirin or levovirin. Interferon-α is included. Preferably, the additional agent active against HCV is interferon-α, or pegylated interferon-α alone or in combination with ribavirin or levovirin.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to compounds, compositions and methods for treating Flaviviridae viruses such as hepatitis C virus infection. However, before describing the present invention in detail, the following terms will first be defined.

Definitions As used herein, the term “alkyl” refers to an alkyl group having 1 to 6 carbon atoms, preferably 1 to 3, more preferably 1 to 2 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl and the like.

  “Substituted alkyl” means alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, oxyacyl, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl An alkyl group having 1 to 3, preferably 1 to 2, substituents selected from the group consisting of ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; means.

  “Alkoxy” refers to the group “alkyl-O—” including, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like.

  “Substituted alkoxy” refers to the group “substituted alkyl-O—”.

“Alkoxyalkyl” refers to -alkylene (alkoxy) _n -alkylene (substituted alkoxy) _n (alkylene is a divalent linear or branched alkylene group of 1 to 3 carbon atoms; alkoxy and substituted alkoxy are as defined herein; And n is an integer of 1 to 2).

  “Acyl” means alkyl-C (O)-, substituted alkyl-C (O)-, alkenyl-C (O)-, substituted alkenyl-C (O)-, alkynyl-C (O)-, substituted alkynyl -C (O)-, cycloalkyl-C (O)-, substituted cycloalkyl-C (O)-, aryl-C (O)-, substituted aryl-C (O)-, heteroaryl-C (O) -, Substituted heteroaryl-C (O), heterocyclic-C (O)-, and substituted heterocyclic-C (O)-.

^{"Acylamino", -C (O) NR 4 R} 4 (R 4 each is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroalkyl Independently selected from the group consisting of aryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and R ⁴ is each linked together with a nitrogen atom to form a heterocycle or substituted heterocycle).

  `` Acyloxy '' refers to alkyl-C (O) O-, substituted alkyl-C (O) O-, alkenyl-C (O) O-, substituted alkenyl-C (O) O-, alkynyl-C (O) O-, substituted alkynyl-C (O) O-, aryl-C (O) O-, substituted aryl-C (O) O-, cycloalkyl-C (O) O-, substituted cycloalkyl-C (O) Means the groups O-, heteroaryl-C (O) O-, substituted heteroaryl-C (O) O-, heterocycle-C (O) O-, and substituted heterocycle-C (O) O- .

  “Oxyacyl” refers to alkyl-OC (O) —, substituted alkyl-OC (O) —, alkenyl-OC (O) —, substituted alkenyl-OC (O) —, alkynyl-OC (O) —, substituted alkynyl -OC (O)-, aryl-OC (O)-, substituted aryl-OC (O)-, cycloalkyl-OC (O)-, substituted cycloalkyl-OC (O)-, heteroaryl-OC (O) -, Substituted heteroaryl-OC (O)-, heterocyclic-OC (O)-, and substituted heterocyclic-OC (O)-.

  `` Alkenyl '' means an alkenyl group preferably having 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms and having at least 1 site, preferably 1 to 2 sites of alkenyl unsaturation To do. Such groups are exemplified by vinyl (ethen-1-yl), allyl, but-3-en-1-yl, and the like.

  “Substituted alkenyl” is alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, provided that no hydroxyl substitution is attached to the vinyl (unsaturated) carbon atom. , Aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, It means an alkenyl group having 1 to 3 substituents, preferably 1 to 2 substituents. Preferred substituted alkenyl groups are selected from, but not limited to, 2,2-difluoroethen-1-yl, 2-methoxyethen-1-yl, and the like.

  It is understood that the term “substituted alkenyl” includes both E (cis) and Z (trans) isomers where appropriate. The isomer may be a pure isomeric compound or a mixture of E and Z components.

  “Alkynyl” means an unsaturated hydrocarbon having at least one site of alkynyl unsaturation and having 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms. Preferred alkynyl groups are ethyn-1-yl, propyn-1-yl, propyn-2-yl, 1-methylprop-2-in-1-yl, butyn-1-yl, butyn-2-yl, butyn-3- Is selected from, but not limited to.

  “Substituted alkynyl” is alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, Alkynyl group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the group consisting of cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle Means. Preferred substituted alkynyl groups are from 2-fluoroethyn-1-yl, 3,3,3-trifluoropropin-1-yl, 3-aminopropyn-1-yl, 3-hydroxypropyn-1-yl, and the like Selected, but not limited to.

“Amino” refers to the group —NH ₂ .

  “Substituted amino” refers to —NR′R ″ (where R ′ and R ″ are not both hydrogen, R ′ and R ″ are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, Independently selected from the group consisting of alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, and R ′ and R ″ are attached thereto To form a heterocyclic or substituted heterocyclic group). When R ′ is hydrogen and R ″ is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When R ′ and R ″ are alkyl, the substituted amino group is as defined herein. Sometimes called dialkylamino.

“Amidino” refers to the group —C (═NR ¹¹ ) NR ¹¹ R ^{11, where} R ¹¹ is independently selected from hydrogen or alkyl.

`` Aminoacyl '' refers to --NR ⁵ C (O) alkyl, --NR ⁵ C (O) substituted alkyl, --NR ⁵ C (O) cycloalkyl, --NR ⁵ C (O) substituted cycloalkyl, --NR ⁵ C (O) alkenyl, --NR ⁵ C (O) substituted alkenyl, --NR ⁵ C (O) alkynyl, --NR ⁵ C (O) substituted alkynyl, --NR ⁵ C (O) aryl, --NR ⁵ C (O) Substituted aryl, —NR ⁵ C (O) heteroaryl, —NR ⁵ C (O) substituted heteroaryl, —NR ⁵ C (O) heterocycle, and —NR ⁵ C (O) substituted heterocycle (R ⁵ is hydrogen) Or a group that is alkyl).

  “Aryl” or “Ar” has a single ring (eg, phenyl) or fused polycycle (eg, naphthyl or anthryl) and the fused ring is aromatic on the condition that the point of attachment is an aromatic carbon. Monovalent aromatic with 6 to 14 carbon atoms, which may or may not be a group (eg 2-benzoxazolinone, 2H-1,4-benzoxazin-3 (4H) -on-7-yl, etc.) Means a carbocyclic group. Preferred aryl include phenyl and naphthyl.

  “Substituted aryl” including “substituted phenyl” means hydroxyl, acyl, acylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, Substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, carboxyl, carboxyl ester, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted Thiocycloalkyl, thioheterocycle, substituted thioheterocycle, cycloalkyl, substituted cycloalkyl, halo, nitro, heteroaryl, substituted heteroaryl, heterocycle, configuration An aryl group substituted with 1 to 3 substituents, preferably 1 to 2 substituents, selected from the group consisting of heterocycle, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, and substituted heterocyclyloxy Or means a phenyl group.

  “Aryloxy” refers to the group aryl-O— that includes, by way of example, phenoxy, naphthoxy, and the like.

  “Substituted aryloxy” refers to substituted aryl-O— groups.

  “Carboxyl” means —COOH or a salt thereof.

  “Carboxyl ester” refers to —C (O) O-alkyl, —C (O) O-substituted alkyl, —C (O) O aryl, and —C (O) O-substituted aryl (alkyl, substituted alkyl, Aryl and substituted aryl are as defined herein).

  “Cycloalkyl” means a cyclic alkyl group of 3 to 10 carbon atoms having a single ring or multiple rings, including by way of example adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like.

  “Substituted cycloalkyl” means oxo (═O), thioxo (═S), alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy 1 to 5 selected from the group consisting of: substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle Means cycloalkyl having one substituent.

  “Cycloalkoxy” refers to —O-cycloalkyl groups.

  “Substituted cycloalkoxy” refers to —O-substituted cycloalkyl groups.

  “Formyl” refers to the group —C (O) H.

“Guanidino” refers to the group —NR ¹² C (═NR ¹² ) NR ¹² R ¹² wherein each R ¹² is independently hydrogen or alkyl.

  “Halo” or “halogen” means fluoro, chloro, bromo and iodo, preferably fluoro or chloro.

“Heteroaryl” has 1 to 10 carbon atoms in the ring and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, provided that nitrogen and / or sulfur is optionally oxidized [(N → O), - S (O) -, or -SO ₂ -], refers to an aromatic group. Such heteroaryl groups can have a single ring (eg, pyridyl or furyl) or fused polycycles (eg, indolizinyl or benzothienyl) provided that the fused ring is attached at the point of attachment through an aromatic ring atom. The conditions may or may not be aromatic and / or may not contain heteroatoms. Preferred heteroaryls include pyridyl, pyrrolyl, indolyl, thiophenyl, and furyl.

  “Substituted heteroaryl” refers to heteroaryl groups that are substituted with from 1 to 3 substituents selected from the same group of substituents as defined for substituted aryl.

  “Heteroaryloxy” refers to the group —O-heteroaryl and “substituted heteroaryloxy” refers to the group —O-substituted heteroaryl.

“Heterocycle” or “heterocyclic” or “heterocycloalkyl” refers to 1 to 10 carbon atoms in the ring and 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. With the exception that nitrogen and / or sulfur may be optionally oxidized [(N → O), —S (O) —, or —SO ₂ —], and the point of attachment in the fused ring system A saturated or unsaturated group (not heteroaryl) having a single ring or multiple condensed rings, where one or more rings can be cycloalkyl, aryl or heteroaryl, provided that it is through a heterocycle.

  “Substituted heterocycle” or “substituted heterocycloalkyl” refers to a heterocycle group substituted with the same 1 to 3 substituents as defined for substituted cycloalkyl.

  Examples of heterocycles and heteroaryls include azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthyl Pyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2 , 3,4-Tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo [b] thiophene, thiazole, thiazolidine, thiophene, Examples include, but are not limited to, nzo [b] thiophene, morpholinyl, thiomorpholinyl (also called thiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl and the like.

  “Heterocyclyloxy” refers to the group —O-heterocycle and “substituted heterocyclyloxy” refers to the group —O-substituted heterocycle.

“Hydrazino” refers to the group —NR ¹³ NR ¹³ R ^{13, where} each R ¹³ is independently selected from the group consisting of hydrogen or alkyl.

"Phosphoric acid (salt)" means -OP (O) (OH) ₂ (monophosphate (salt) or phospho), -OP (O) (OH) OP (O) (OH) ₂ (diphosphoric acid (Salt) or diphospho) and -OP (O) (OH) OP (O) (OH) OP (O) (OH) ₂ (triphosphate) or a salt containing a partial salt thereof means. Of course, it is understood that the first oxygen of mono-, di- and triphosphates (salts) (phospho, diphospho and triphospho) contains the oxygen atom at the 5-position of the ribose sugar.

  “Phosphate ester” means the aforementioned mono-, di- and triphosphate groups in which one or more hydroxyl groups are substituted with alkoxy groups.

“Phosphonic acid (salt)” means —OP (O) (R ⁶ ) (OH) or —OP (O) (R ⁶ ) (OR ⁶ ) or a salt containing a partial salt thereof (R ⁶ is hydrogen, Group independently selected from alkyl, substituted alkyl, carboxylic acid, and carboxyl ester). It will be appreciated that the initial oxygen of the phosphonic acid (salt) contains the oxygen atom at the 5-position of the ribose sugar.

（式中、R⁷はそれぞれ同じでも異なっていてもよく、それぞれ水素、アルキル、置換アルキル、シクロアルキル、または置換シクロアルキルである）。特に好ましいホスホロジアミデートは下記の基である。

“Phosphorodiamidate” means the following groups:

(Wherein R ⁷ may be the same or different and each is hydrogen, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl). Particularly preferred phosphorodiamidates are the following groups:

“Phosphoramidate monoester” refers to the following group wherein R ³⁰ is as defined above and R ⁸ is hydrogen or alkyl. In a preferred embodiment, R ³⁰ is derived from an L-amino acid.

“Phosphoramidate diester” means that R ³⁰ is as defined above, R ⁸ is hydrogen or alkyl, and R ¹⁰ is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, The following groups selected from the group consisting of heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are meant. In a preferred embodiment, R ³⁰ is derived from an L-amino acid.

“Cyclic phosphoramidate” means the following groups, wherein n is 1 to 3, more preferably n is 1 to 2.

“Cyclic phosphorodiamidate” means the following group, wherein n is 1 to 3, more preferably n is 1 to 2.

“Phosphonamidate” refers to the group: R ¹⁴ is hydrogen, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl.

  “Thiol” refers to the group —SH.

  “Thioalkyl” or “alkylthioether” or “thioalkoxy” refers to the group —S-alkyl.

  “Substituted thioalkyl” or “substituted alkylthioether” or “substituted thioalkoxy” refers to the group —S-substituted alkyl.

  “Thiocycloalkyl” refers to the group —S-cycloalkyl, and “substituted thiocycloalkyl” refers to the group —S-substituted cycloalkyl.

  “Thioaryl” refers to the group —S-aryl, and “substituted thioaryl” refers to the group —S-substituted aryl.

  “Thioheteroaryl” refers to the group —S-heteroaryl and “substituted thioheteroaryl” refers to the group —S-substituted heteroaryl.

  “Thioheterocycle” refers to the group —S-heterocycle, and “substituted thioheterocycle” refers to the group —S-substituted heterocycle.

The term “amino acid side chain” means the R ³⁰ substituent of an α-amino acid of the formula NH ₂ CH (R ³⁰ ) COOH, wherein R ³⁰ is from the group consisting of hydrogen, alkyl, substituted alkyl, aryl and substituted aryl. Preferably, the α-amino acid side chain is one side chain of 20 natural L amino acids.

  The term “pharmaceutically acceptable prodrug” means an art-recognized modification to one or more functional groups that are metabolized in vivo to yield a compound of the invention or Provides its active metabolite. Such functional groups are well known in the art and have hydroxyl and / or amino substituted acyl groups, one or more side chain hydroxyl groups converted to alkoxy, substituted alkoxy, aryloxy or substituted aryloxy groups. Including esters of mono-, di- and triphosphates.

  The term “pharmaceutically acceptable salt” refers to a pharmaceutically acceptable salt of a compound, which salt is well known in the art and is by way of example only, sodium, potassium, calcium, magnesium, Derived from various organic and inorganic counterions, including ammonium, tetraalkylammonium, etc .; if the molecule contains a basic functional group, hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate , And salts of organic or inorganic acids such as oxalate.

  The term “pharmaceutically acceptable partial salt” allows a plurality of groups to form a salt, but less than the maximum amount of such groups actually has a substituent forming a salt. Means a compound. For example, diphospho groups can form a plurality of salts, and when only partially ionized, the resulting groups are sometimes referred to herein as partial salts.

  In all substituted groups as defined above, polymers resulting from defining substituents with further substituents to themselves (for example, substituted aryl groups as substituents that are themselves substituted with substituted aryl groups) It is understood that the present invention is not intended to include such as substituted aryl having). In such cases, the maximum number of such substituents is three. That is, each of the above definitions is constrained by a limitation that, for example, a substituted aryl group is limited to -substituted aryl- (substituted aryl) -substituted aryl.

  Similarly, it is understood that the foregoing definitions are not intended to include unacceptable substitution patterns (eg, methyl substituted with 5 fluoro groups or a hydroxyl group of α for ethenyl or acetylenic unsaturation). Such unacceptable substitution patterns are well known to those skilled in the art.

General Synthetic Methods The compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (ie reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are indicated, it is understood that other process conditions may be used unless otherwise specified. Seem. Optimum reaction conditions may vary depending on the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

  In addition, as will be apparent to those skilled in the art, conventional protecting groups may be required to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as conditions suitable for protecting and deprotecting particular functional groups are well known in the art. For example, many protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.

  In addition, the compounds of the present invention contain one or more chiral centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, ie as individual enantiomers or diastereomers, or as a mixture enriched in one stereoisomer. it can. All such stereoisomers (or mixtures enriched therewith) are included within the scope of the invention, unless otherwise indicated. Pure stereoisomers (or mixtures rich in them) may be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolution reagents, and the like.

  The starting materials for the following reactions are generally known compounds or can be prepared by known methods or obvious variations thereof. For example, many of the starting materials are available from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA), Bachem (Trans, CA, USA), Emka-Chemce, or Sigma (St. Louis, MO, USA). Others are Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and methods described in standard reference texts such as Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or It may be prepared by obvious variations. In particular, the compounds of the present invention can generally be prepared by various methods known in the field of organic chemistry, particularly nucleoside and nucleotide analog synthesis. General reviews of nucleoside and nucleotide analog preparation include: 1) Michelson AM "The Chemistry of Nucleosides and Nucleotides," Academic Press, New York, 1963; 2) Goodman L. "Basic Principles in Nucleic Acid Chemistry , "Academic Press, New York, 1974, vol. 1, Ch. 2; and 3)" Synthetic Procedures in Nucleic Acid Chemistry, "Eds. Zorbach W. & Tipson R., Wiley, New York, 1973, vol. 1 & 2.

  The synthesis of the compounds of the invention generally follows either a convergent or linear synthetic route as described below.

  Strategies available for synthesis of the compounds of the present invention include, for example:

（式中、T、Y、W、W¹、およびW²は前述の定義のとおりである）は、下記の一般法の一つによって調製することができる。 General synthesis of 2'-C-branched nucleosides 2'-C-branched ribonucleosides of formula I:

(Wherein T, Y, W, W ¹ and W ² are as defined above) can be prepared by one of the following general methods.

Convergent approach: Glycosylation of nucleobases with appropriately modified sugars The key starting material for this method is 2'-OH and 2'-H, with an appropriate leaving group at position 1, eg acyl An appropriately substituted sugar having a group or a chloro, bromo, fluoro, or iodo group. Sugars can be purchased or prepared by any known means including standard epimerization, substitution, oxidation and / or reduction techniques. For example, commercially available 1,3,5-tri-O-benzoyl-α-D-ribofuranose (Pfanstiel Laboratories, Inc.) can be used. The substituted sugar can then be oxidized with a suitable oxidizing agent in a compatible solvent at a suitable temperature to yield a 2'-modified sugar. Possible oxidizing agents are, for example, Dess-Martin-Periodine reagent, Ac ₂ O + DCC in DMSO, swarnidation (DMSO, oxalyl chloride, triethylamine), Jones reagent (mixture of chromic acid and sulfuric acid), Collins reagent (dipyridine oxidized Cr Phases such as (VI), Corey reagent (pyridinium chlorochromate), pyridinium dichromate, dichromate, potassium permanganate, MnO ₂ , ruthenium tetroxide, chromic acid or permanganate immobilized on the polymer Transfer catalyst, Cl ₂ -pyridine, H ₂ O ₂ -ammonium molybdate, NaBrO ₂ -CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Merwine-Pondruf-Burley reagent (aluminum t -Butoxide and another ketone) and N-bromosuccinimide.

Coupling of a ketone with a Grignard reagent, organolithium, lithium dialkylcopper or organometallic carbon nucleophile such as SiMe _{4 in} TBAF in a suitable aprotic solvent at a suitable temperature and 2'-methyl Get sugar. For example, CH ₃ MgBr / TiCl ₄ or CH ₃ MgBr / CeCl ₃ can be used as described in Wolfe et al. 1997. J. Org. Chem. 62: 1754-1759. Methylated sugars can be synthesized by suitable protecting groups, preferably acyl, substituted, by methods well known to those skilled in the art as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. It can be optionally protected with an acyl or silyl group.

  The optionally protected sugar can then be coupled to the purine base by methods well known to those skilled in the art, as taught by Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, acylated sugars can be coupled to silylated bases with Lewis acids such as tin tetrachloride, titanium tetrachloride or trimethylsilyl triflate in a suitable solvent at a suitable temperature. Alternatively, the halosugar can be coupled to a silylated base in the presence of trimethylsilyl triflate.

In addition to the foregoing, 2'-C-substituted sugar used in the synthetic methods described herein are well known in the art, for example, it is described Sommadossi, et al. ¹⁰ and Carrol, by et al. ^{11, 12} All of which are hereby incorporated by reference in their entirety.

式中、Phはフェニルであり、Xはハロなどの適当な脱離基である。 Scheme 1 below describes another synthesis of protected sugars useful for coupling to the bases described herein.
Scheme 1

Where Ph is phenyl and X is a suitable leaving group such as halo.

The formation of sugar a in Scheme 1 above is achieved as described by Mandal, SB, et al., Synth. Commun., 1993, 9, page 1239 starting from commercially available D-ribose. Protection of the hydroxyl group to form sugar b is described in Witty, DR, et al., Tet. Lett., 1990, 31, page 4787. Sugars c and d are prepared using the method of Ning, J. et al., Carbohydr. Res., 2001, 330, page 165, and the methods described herein. Sugar e is prepared by using a modification of the Grignard reaction with a suitable organometallic described (titanium / cerium is not required) in CH ₃ MgBr or herein. Finally, the halogenated sugar (X = halo) used in the next coupling reaction is prepared using the same protection method used in the preparation of sugar b above. Halogenation is described in Seela, US Pat. No. 6,211,158.

  Subsequently, any of the aforementioned nucleosides can be deprotected by methods well known to those skilled in the art as taught by Greene et al. Protective Groups in Organic Synthesis, Jon Wiley and Sons, Second Edition, 1991. .

Details of another approach for preparing protected sugars useful for coupling to heterocyclic bases are shown in Scheme 2 below.
Scheme 2

  In Scheme 2, methylation of the hydroxyl group of Compound 1 proceeds by conventional methods to give Compound 2. The 2, 3 and 5 hydroxyl groups of Compound 2 are each protected with 2,4-dichlorobenzyl group to give Compound 3. Selective deprotection of the 2- (2 ', 4'-dichlorobenzyl) group of compound 3 in contact with stannous chloride in a suitable solvent such as methylene chloride or chloroform at low temperature, for example, about 0 to 5 ° C. To complete the reaction, for example, for 24-72 hours. Oxidation of the 2-hydroxyl group proceeds as described herein to provide compound 7. Methylation is also performed as described herein to give compound 8.

Linear approach: Modification of pre-generated nucleosides The key starting material for this method is appropriately substituted nucleosides with 2'-OH and 2'-H. Nucleosides can be purchased or prepared by any known means, including standard coupling methods. Nucleosides can be prepared by methods known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, by suitable protecting groups, preferably acyl, substituted alkyl or It can also be optionally protected with a silyl group.

The appropriately protected nucleoside can then be oxidized with a suitable oxidizing agent in a compatible solvent at a suitable temperature to yield a 2'-modified sugar. Possible oxidizing agents are, for example, Dess-Martin-Periodine reagent, Ac ₂ O + DCC in DMSO, swarnidation (DMSO, oxalyl chloride, triethylamine), Jones reagent (mixture of chromic acid and sulfuric acid), Collins reagent (dipyridine oxidized Cr Phases such as (VI), Corey reagent (pyridinium chlorochromate), pyridinium dichromate, dichromate, potassium permanganate, MnO ₂ , ruthenium tetroxide, chromic acid or permanganate immobilized on the polymer Transfer catalyst, Cl ₂ -pyridine, H ₂ O ₂ -ammonium molybdate, NaBrO ₂ -CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Merwine-Pondruf-Burley reagent (aluminum t -Butoxide and another ketone) and N-bromosuccinimide.

Coupling of organometallic carbon nucleophiles such as Grignard reagents, organolithium, lithium dialkylcopper or CH ₃ SiMe _{3 in} TBAF with ketones in an appropriate aprotic solvent at an appropriate temperature for alkyl substitution A nucleoside is obtained. Isolation of an appropriate isotope is performed as necessary.

  Subsequently, the nucleosides can be deprotected by methods well known to those skilled in the art as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

  In one embodiment of the invention, the D-enantiomer is preferred. However, it is contemplated that the L-enantiomer is also useful herein. L-enantiomers corresponding to the compounds of the invention can be prepared according to the same general procedure described above, starting with the corresponding L-sugar or nucleoside as starting material. In certain embodiments, 2'-C-branched ribonucleosides are desirable.

The compounds of the present invention can generally be prepared by a variety of methods known in the field of organic chemistry, particularly nucleoside and nucleotide analog synthesis. Starting materials for the synthesis are readily available from commercial sources or are known or can be prepared by techniques known in the art. A general review of nucleoside and nucleotide analog preparation includes the following:
Michelson AM "The Chemistry of Nucleosides and Nucleotides," Academic Press, New York, 1963.
Goodman L. "Basic Principles in Nucleic Acid Chemistry," Academic Press, New York, 1974, vol. 1, Ch. 2.
"Synthetic Procedures in Nucleic Acid Chemistry," Eds. Zorbach W. & Tipson R., Wiley, New York, 1973, vol. 1 & 2.

  The 5-substituted acetylenyl-pyrrolo [2,3-d] pyrimidinyl nucleoside derivatives of the present invention can be synthesized using the method shown in Scheme 3 below.

  A convergent approach to prepare pyrrolo [2,3-d] pyrimidinyl nucleosides is shown in Scheme 3 below. First, commercially available 4-chloropyrrolo [2,3-d] pyrimidine 11 is obtained by a well-known method, for example, a halogenation method described in A. Gangjee et al., J. Med. Chem. (2003) 46, 591. Halogenated at the 5-position (compound 12). Intermediate compound 12 may be isolated and purified using standard methods such as chromatography, precipitation, crystallization, filtration and the like. Alternatively, compound 12 may be isolated and used in the next step without further purification.

  5- (Substituted alkynyl) -4-chloropyrrolo [2,3-d] pyrimidine 13 was prepared using the Sonigashira condition described in A. Gangjee et al., (J. Med. Chem. (2003) 46, 591). Prepare compound 13 Intermediate compound 13 may be isolated and purified using standard methods such as chromatography, precipitation, crystallization, filtration and the like. Alternatively, compound 13 may be isolated and used in the next step without further purification.

Compound 13 is coupled to protected 2-methyl substituted sugar 8 (the synthesis of which is described above and described by Carroll, et al., ¹¹ , ¹² ) using conditions well known in the art. For example, 1-O-methyl-3,5-bis-O- (2,4-dichlorophenylmethyl) -2'-C-methyl-β-D-ribofuranoside 8 is added to anhydrous anhydrous dichloromethane, chloroform, carbon tetrachloride, etc. Dissolve in an inert solvent and then cool the solution to about 0 ° C. Thereafter, excess HBr in acetic acid or other suitable reagent is added dropwise. This reaction is typically carried out at about 0 ° C. for about 1 hour or at ambient temperature for about 2.5 hours or until substantially complete as determined by conventional techniques such as tlc. The resulting brominated sugar mixture is isolated and purified using standard methods such as chromatography, precipitation, crystallization, filtration and the like. Alternatively, this intermediate may be isolated and used in the next step without further purification. The resulting brominated sugar mixture is preferably coevaporated with anhydrous toluene, dissolved in a suitable inert diluent such as anhydrous acetonitrile, and stirred with the sodium salt of compound 13 overnight. The sodium salt of compound 13 is prepared by suspending compound 13 in an anhydrous inert solvent such as acetonitrile with NaH dispersed in oil in an inert atmosphere. The reaction is conducted at a temperature of about 0 ° C. to about 40 ° C. for about 2 to about 24 hours. Finally, compound 15 is isolated and purified using standard methods such as chromatography, precipitation, crystallization, filtration and the like. Alternatively, this intermediate may be isolated and used in the next step without further purification.

式中、Rは本明細書の定義のとおりであり、DCBは2,4-ジクロロベンジルである。 Deprotection of compound 15 using standard methods yields compound 16, which in some cases is converted to the 4-amino derivative (compound 17) using methods well known in the art. For example, compound 16 is added to liquid ammonia at about −80 ° C. and warmed at about 80 ° C. for about 24 to about 48 hours. Compound 17 is isolated and purified using standard methods such as chromatography, precipitation, crystallization, filtration and the like.
Scheme 3

Where R is as defined herein and DCB is 2,4-dichlorobenzyl.

  In another approach, the 1- [5- (substituted alkynyl) -4-aminopyrrolo [2,3-d] pyrimidine] -2′-C-methyl-β-D-ribofuranoside compound is a method shown in Scheme 4 below. Can be prepared.

  Compound 12 prepared as described above is coupled to protected sugar 8 using the method described for the preparation of compound 15 in Scheme 3 above to give compound 19. Compound 19 is deprotected using standard methods to give compound 20.

  From compound 20, a 1- [5- (substituted alkynyl) -4-amino-pyrrolo [2,3-d] pyrimidine] -2′-C-methyl-β-D-ribofuranoside compound is first prepared according to Scheme 3 above. The 4-chloro group was converted to an amino group using the method described for the preparation of compound 17 from compound 16 to give compound 21, followed by A. Gangjee et al., (J. Med. Chem. (2003 ) 46, 591) to produce the substituted alkynyl derivative, compound 17, by coupling using the Sonigashira conditions described in 46, 591).

式中、RおよびDCBは前述のとおりである。 In some cases, the 1- [5- (substituted alkynyl) -4-amino-pyrrolo [2,3-d] pyrimidine] -2′-C-methyl-β-D-ribofuranoside compound is obtained from compound 20, It can be prepared by first converting the 5-iodo group to a 5-substituted alkynyl derivative (Compound 16) and then converting the 4-chloro group to an amine (Compound 17). Details of each of these conversion methods are as described above.
Scheme 4

In the formula, R and DCB are as described above.

Performed for using the compound prepared in Scheme 3 and 4 above as a starting material, W, preparation of W ¹ or W ² is other than hydrogen, using the method described in the following review of prodrug preparation be able to:
1) Cooperwood, JS et al., "Nucleoside and Nucleotide prodrugs," in Ed (s) Chu, CK Recent Advances in Nucleosides (2002), 92-147.
2) Zemlicka, J. et al., Biochimica et Biophysica Acta (2002), 158 (2-3), 276-286.
3) Wagner, C. et al., Medicinal Research Reviews (2002), 20 (6), 417-451.
4) Meier, C. et al., Synlett (1998), (3), 233-242.

For example, 1- [5- (substituted alkynyl) -4-amino-pyrrolo [2,3-d] pyrimidine] -2′-C-methyl-β-D-ribofuranoside compound 5′-hydroxyl group phospho, diphospho Or the conversion to the triphospho-analogue is described by DW Hutchinson, (Ed. Leroy b. Townsend) "The Synthesis, reaction and Properties of Nucleoside Mono-, Di-, Tri-, and tertaphosphate and Nucleosides with Changes in the Phosphoryl Residue, It can be prepared using the method described in Chemistry of Nucleosides and Nucleotides, Plenum Press, (1991) 2 .

Preparation of amino acids on ribofuranoside can be accomplished as shown in Scheme 5 below.
Scheme 5

  The desired Boc protected amino acid and N, N′-carbonyldiimidazole are dissolved in an inert solvent such as THF. The reaction mixture is maintained between about 20 and about 40 ° C. for about 0.5 to 24 hours. A solution containing a slight excess of the desired nucleoside in an inert solvent such as DMF is added to the Boc protected amino acid mixture and heated at about 40 to about 80 ° C. for about 2 to about 24 hours. A mixture of structural isomers is isolated and separated using conventional methods such as evaporation, precipitation, filtration, crystallization, chromatography and the like.

  The desired ester is then acidified, for example, using a 1: 1 v / v TFA / DCM solution at about 20 to about 40 ° C. for about 0.1 to about 1 hour and evaporated. The residue is dissolved in water and maintained at about 0 to about 30 ° C. for about 2 to about 24 hours. Standard methods and conditions can be used to separate the mixture and the desired product can be isolated by RP-HPLC.

式中、Tは前述の定義のとおりである。 Although the above scheme shows the generation of a deazapurine prodrug, this method can be used with any desired nucleoside compound. Similarly, the amino acid may be protected with any protecting group suitable for the reaction conditions. These protecting groups are well known in the art.
Scheme 6

In the formula, T is as defined above.

  Compound 1 is dissolved in an anhydrous solvent such as pyridine, and a silyl halide such as tert-butylchlorodiphenylsilane is added to generate a protecting group at the 5 ′ position of the sugar. Any protecting group can be used that can be directed to the 5 'position and can be removed orthogonally to the final desired 3'-ester. The reaction is conducted at a temperature of about 10 to about 40 ° C. for about 4 to about 24 hours. The desired acyl chloride is added to the protected nucleoside, Compound 30, and stirred for about 4 to about 24 hours to produce Compound 31. This can be isolated and purified using standard methods such as isolation, crystallization, extraction, filtration, chromatography and the like. Compound 32 is prepared by removing the protecting group at the 5 ′ position. This can be achieved by reacting compound 30 with a 1M solution of tetrabutylammonium fluoride in THF. The final product is isolated and purified using standard methods such as isolation, crystallization, extraction, filtration, chromatography and the like.

  Although the above scheme shows the generation of a deazapurine prodrug, this method can be used with any desired nucleoside compound.

Utility, testing, and administration
Utility The present invention provides novel compounds having antiviral activity, including hepatitis C virus. The compounds of the present invention inhibit viral replication by inhibiting enzymes involved in replication, including RNA-dependent RNA polymerase. The compounds of the present invention may also inhibit other enzymes used in the activity or growth of Flaviviridae viruses such as HCV.

  The compounds of the present invention can also be used as prodrug nucleosides. Thus, they can be taken up by cells and phosphorylated by kinases in the cells to triphosphates, then inhibitors of polymerase (NS5b) and / or act as chain terminators.

  The compounds of the present invention may be used alone or in combination with other compounds for treating viruses.

Administration and Pharmaceutical Composition In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the compound of the invention, i.e., the active ingredient, depends on the severity of the disease being treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors. It depends on the factors. The drug can be administered multiple times a day, preferably once or twice a day.

  The therapeutically effective amount of the compound of formula I is in the range of about 0.05 to 50 mg / kg recipient body weight per day, preferably about 0.01 to 25 mg / kg / day, more preferably about 0.5 to 10 mg / kg / day. It can be. Thus, for administration to a 70 kg person, the dose range is most preferably about 35-70 mg per day.

  In general, the compounds of the invention will be administered as a pharmaceutical composition by any one of the following routes: oral, systemic (eg, transdermally, intranasally, or by suppository), or parenterally ( (For example, intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a conventional daily dosage regimen which can be adjusted according to the degree of affliction. The composition may take the form of tablets, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition. Another preferred mode for administering the compounds of the invention is inhalation. This is an effective method for delivering therapeutic agents directly to the respiratory tract (see US Pat. No. 5,607,915).

  The choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug. For delivery by inhalation, the compounds can be formulated as solutions, suspensions, aerosol propellants or dry powders and filled into a suitable dispenser. There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (MDI) and dry powder inhalers (DPI). Nebulizer devices generate a high velocity air stream that sprays the therapeutic agent (formulated in a liquid dosage form) as a mist that is carried into the patient's respiratory tract. An MDI is a formulation that is typically packaged with a pressurized gas. After activation, the device releases a metered therapeutic agent by pressurized gas, providing a reliable and consistent method of drug administration. The DPI releases the therapeutic agent in the form of a flowable powder that can be dispersed in the patient's inspiratory airflow during breathing by the device. In order to obtain a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose. The weighed therapeutic agent is stored in capsule form and delivered with each actuation.

  Recently, based on the principle that bioavailability can be increased by increasing the surface area, ie by reducing the particle size, pharmaceutical formulations have been developed, especially for drugs with low bioavailability. For example, US Pat. No. 4,107,288 describes a pharmaceutical formulation having particles ranging in size from 10 to 1,000 nm, where the active substance is supported on a polymeric cross-linked substrate. US Pat. No. 5,145,684 describes the manufacture of pharmaceutical formulations, where the drug is micronized into nanoparticles (average particle size 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium, which is significantly higher A pharmaceutical formulation with bioavailability is obtained.

  The composition generally consists of a combination of a compound of formula I and at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration and do not adversely affect the therapeutic benefit of the compound of formula I. Such excipients can be any solid, liquid, semi-solid, or gaseous excipient in the case of aerosol compositions generally available to those skilled in the art.

  Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearic acid, sodium chloride, Includes nonfat dry milk. Liquid and semi-liquid excipients are selected from a variety of oils including glycerol, propylene glycol, water, ethanol and petroleum, animal oils, vegetable oils, or synthetic oils such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Also good. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

  Pressurized gas may be used to disperse the compounds of the present invention in an aerosol dosage form. Inert gases suitable for this purpose are nitrogen, carbon dioxide and the like. Other suitable pharmaceutical excipients and their formulations are described in E. W. Martin, edited by Remington's Pharmaceutical Sciences (Mack Publishing Company, 18th ed., 1990).

  The amount of the compound in the formulation can vary within the full range employed by those skilled in the art. Typically, the formulation comprises from about 0.01 to 99.99% by weight of the compound of Formula I, based on weight percent (% by weight), with the remainder being one or more suitable pharmaceutical excipients. . Preferably, the compound is present at a level of about 1-80% by weight. Exemplary pharmaceutical formulations comprising a compound of formula I are described below.

In addition, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of another active agent against RNA-dependent RNA viruses, particularly HCV. To do. Substances active against HCV include ribavirin, levovirin, viramidine, thymosin α-1, inhibitors of HCV NS3 serine protease, interferon-α, pegylated interferon-α (peginterferon-α), interferon-α and ribavirin A combination of peginterferon-α and ribavirin, a combination of interferon-α and levovirin, and a combination of peginterferon-α and levovirin, but are not limited thereto. Interferon-α includes recombinant interferon-α2a (Hoffman-LaRoche, Roferon, which is an interferon available from Natley, NJ), and interferon-α2b (Schering Corp., Intron, an interferon available from Kenilworth, NJ, USA) -A), consensus interferon, and purified interferon-alpha products, including but not limited to. For a discussion of ribavirin and its activity against HCV, see JO Saunders and SA Raybuck, "Inosine Monophosphate Dehydrogenase: Consideration of Structure, Kinetics and Therapeutic Potential," Ann. Rep. Med. Chem., 35 : 201-210 (2000). Please refer.

Examples Throughout the following examples as well as throughout the application, the following abbreviations have the following meanings. If not defined, the term has its generally accepted meaning.
AcOH or HOAc = acetic acid
Ac ₂ O = acetic anhydride
Ar = aryl hydrogen
atm = atmospheric pressure
Boc = t-butoxycarbonyl
bs = wide single line
CAN = cerium (IV) ammonium nitrate
cm = centimeter
d = double wire
con = concentration
DCM = dichloromethane
dd = double line double line
DMF = dimethylformamide
dt = triple line double line
DBU = 1,8-diazabicyclo [5.4.0] undec-7-ene
DCB = 2,4-dichlorobenzyl
DCC = dicyclohexylcarbodiimide
DMEM = Dulbecco's smallest eagle medium
DMSO = dimethyl sulfoxide
DTT = Dithiothreitol
EDTA = ethylenediaminetetraacetic acid
eq. or eq = equivalent
g = grams
h or hr = time
HCV = hepatitis C virus
HPLC = high performance liquid chromatography
IPTG = isopropyl β-D-1-thiogalactopyranoside
IU = International unit
kb = kilobase
kg = kilogram
KOAc = potassium acetate
L = liter
M = Multiple wire
M = Molar concentration
Me = methyl
MeOH = methanol
min = minute
mg = milligram
mL = milliliter
mm = mm
mM = mmol concentration
mmol = mmol
MS = mass spectrum
ng = nanogram
N = regulation
nm = nanometer
nM = nanomolar concentration
NMR = nuclear magnetic resonance
NTA = nitrilotriacetic acid
NTP = nucleotide triphosphate
RP HPLC = reversed-phase high-performance liquid chromatography
q = quadruple wire
s = single line
t = triple line
TBAF = tetrabutylammonium fluoride
TEA = Triethylamine
TFA = trifluoroacetic acid
THF = tetrahydrofuran
tlc or TLC = thin layer chromatography
T _m = melting temperature
UTP = uridine triphosphate μL = microliter μg = microgram μM = micromolar concentration
v / v = volume ratio
w / w = weight ratio
Wt% = weight percent

  In addition, all reactions and melting temperatures are in degrees Celsius unless otherwise noted.

Throughout the examples below as well as throughout this application, the claimed compounds use the following numbering system:

段階1：1-O-メチル-2,3,5-トリス-O-(2,4-ジクロロベンジル)-β-D-リボフラノースの調製
標題化合物を、Marin, P.; Helv. Chim. Acta, 1995, 78, 486に記載の方法を用い、市販のD-リボースから出発して合成した。 Example 1
Preparation of intermediate 1-O-methyl-2-methyl-3,5-bis-O- (2,4-dichlorobenzyl) -β-D-ribofuranose

Step 1: Preparation of 1-O-methyl-2,3,5-tris-O- (2,4-dichlorobenzyl) -β-D-ribofuranose The title compound was prepared from Marin, P .; Helv. Chim. Acta , 1995, 78, 486, starting from commercially available D-ribose.

Step 2: Preparation of 1-O-methyl-3,5-bis-O- (2,4-dichlorobenzyl) -β-D-ribofuranose
To a solution of the product of Step 1 (171.60 g, 0.2676 mol) in methylene chloride (1.8 L) cooled to 0 ° C., stir a solution of tin chloride (31.522 mL, 0.2676 mol) in methylene chloride (134 mL). It was added dropwise. After maintaining the solution at about 3 ° C. for about 27 hours, tin chloride (SnCl ₄ ) (5.031 mL, 0.04282 mol) was added and the solution was maintained at about 3 ° C. overnight. After about 43 hours total reaction time, the reaction was quenched by careful addition of saturated NaHCO ₃ solution (1.9 L). The tin salt was removed by filtration through celite, after which the organic phase was isolated, dried over MgSO ₄ and evaporated under reduced pressure. The yield of untreated dark yellow oil was 173.6 g. The crude oil was used directly in the next step without further purification.

Step 3: Preparation of 1-O-methyl-2-oxo-3,5-bis-O- (2,4-dichlorobenzyl) -β-D-ribofuranose Dess Martin in anhydrous methylene chloride (740 mL) A solution of periodinane (106.75 g, 0.2517 mol) was ice-cooled under an argon atmosphere, and to this was added a solution of the product of step 2 above in anhydrous methylene chloride (662 mL) over 0.5 h. The reaction mixture was stirred at 0 ° C. for 0.5 h and then at room temperature for 6 days. The mixture was diluted with anhydrous diethyl ether (1.26 L) and then poured into an ice-cold solution of Na ₂ S ₃ O ₃ .5H ₂ O (241.2 g, 1.5258 mol) in saturated aqueous sodium bicarbonate (4.7 L). The layers are separated and the organic layer is washed with saturated aqueous sodium bicarbonate (1.3 L), water (1.7 L) and brine (1.3 L), dried over MgSO ₄ , filtered and evaporated to remove the target compound. Obtained. The compound (72.38 g, 0.1507 mol) was used in the next step without further purification.

Step 4: Preparation of the title compound
A solution of MeMgBr in anhydrous diethyl ether (500 mL) maintained at −55 ° C. was added dropwise to a solution of the product from Step 3 above (72.38 g, 0.1507 mol) in anhydrous diethyl ether (502 mL) as well. The reaction mixture was warmed to −30 ° C., mechanically stirred from about −30 ° C. to −15 ° C. for 4 hours and then poured into ice cold water (2 L). After stirring vigorously for 0.5 h at ambient temperature, the mixture was filtered through a celite pad (14 × 5 cm) and the celite was washed thoroughly with diethyl ether. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue is dissolved in hexane (approx. 1 mL per gram of crude product), adsorbed onto a silica gel column (1.5 L silica gel in hexane) and eluted with hexane and hexane: ethyl acetate 4: 1 (v / v) for final purification 53.58 g (0.1080 mol) of product was obtained. The form of the title compound was a dark yellow viscous oil;
MS: m / z 514.06 (M + NH ₄ +).

段階1. 4-クロロ-5-ヨード-7H-ピロロ[2,3-d]ピリミジン：
4-クロロ-7H-ピロロ[2,3-d]ピリミジン（10.75g、70mmol）およびN-ヨードスクシンイミド（16.8g、75mmol）を無水DMF（400mL）に溶解し、周囲温度で暗所に一晩放置した。溶媒を蒸発させた。黄色残渣をNa₂SO₃の10％熱溶液に懸濁し、ろ過し、熱水で二回洗浄し、エタノールから結晶化して、標題化合物（14.6g、74.6％）をオフホワイト結晶で得た。母液を1/3量まで蒸発させ、エタノールから再度結晶化して、標題生成物（2.47g、12.3％）を得た。合計収率は100％に近かった。

Example 2
Preparation of 7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5- [2- (trimethylsilyl) ethyn-1-yl] -pyrrolo [2,3-d] pyrimidine

Step 1. 4-Chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine:
4-Chloro-7H-pyrrolo [2,3-d] pyrimidine (10.75 g, 70 mmol) and N-iodosuccinimide (16.8 g, 75 mmol) are dissolved in anhydrous DMF (400 mL) and overnight in the dark at ambient temperature. I left it alone. The solvent was evaporated. The yellow residue was suspended in a 10% hot solution of Na ₂ SO ₃ , filtered, washed twice with hot water and crystallized from ethanol to give the title compound (14.6 g, 74.6%) as off-white crystals. The mother liquor was evaporated to 1/3 volume and recrystallized from ethanol to give the title product (2.47 g, 12.3%). The total yield was close to 100%.

Step 2. 7- (2'-Methyl-3 ', 5'-bis-O- (2,4-dichlorobenzyl-β-D-ribofuranosyl) -4-chloro-5-iodo-pyrrolo [2,3- d] Pyrimidine:
The base obtained as described above (11.2 g, 40 mmol) was suspended in CH ₃ CN (500 mL), NaH (1.6 g, 40 mmol, 60% in oil) was added and the reaction mixture was dissolved at room temperature until the NaH was dissolved ( Stir for about 2 hours. 1-O-methyl-2-methyl-3,5-bis-O- (2,4-dichlorobenzyl) -β-D-ribofuranose (10 g, 20 mmol) is dissolved in DCM (500 mL) and ice / water bath Cooled to 4 ° C. HBr _(g) was bubbled through the solution for about 30 minutes. The reaction was monitored by TLC and performed until the starting sugar disappeared (ether / hexane 1: 9 v / v). After the reaction was complete, the solvent was evaporated at a temperature below 20 ° C. and maintained under high vacuum for 20 minutes to remove traces of HBr. The base Na salt solution was rapidly filtered and the filtrate was added to the sugar component. The reaction was continued overnight at ambient temperature, neutralized with 0.1 NH ₂ SO ₄ and evaporated. The residue was partitioned between ethyl acetate (700 mL) and water (700 mL). The organic fraction was washed with water (150 mL), brine (150 mL), dried over Na ₂ SO ₄ and evaporated to give a semi-crystalline mixture. Toluene (500 mL) was added to give a pale tan precipitate (2.5 g, 25%) of unreacted heterocyclic base. The filtrate was concentrated to a volume of 50 mL and added to a glass filter packed with silica gel (10 × 10 cm). The filter was washed with 10% ethyl acetate in toluene and a 500 mL fraction was collected. Fractions 2-4 contained the title compound and fractions 6-7 contained heterocyclic bases.

Fractions 2-4 were evaporated, ether was added to the colorless oil and the mixture was sonicated for 5 minutes. An off-white precipitate formed (yield 7.4 g, 50%), the mother liquor was evaporated and the above procedure was repeated to give an additional 0.7 g of the title nucleoside. The total yield is 8.1 g (54.4%).

Step 3. 7- (2′-Methyl-β-D-ribofuranosyl) -4-chloro-5-iodo-pyrrolo [2,3-d] pyrimidine:
A solution of the compound from the previous step (8 g, 10.7 mmol) in DCM (200 mL) was cooled to −78 ° C., and boron trichloride (1 M in DCM, 88 mL, 88 mmol) was added dropwise thereto. The mixture was stirred at −78 ° C. for 2.5 hours and at −20 ° C. overnight. MeOH / DCM (90 mL, 1: 1) was added to quench the reaction and the resulting mixture was stirred at −20 ° C. for 30 minutes and then neutralized with aqueous ammonia at the same temperature. The solid was filtered and washed with methanol / DCM (250 mL, 1: 1). The filtrate was mixed with silica gel (50 mL) and evaporated to dryness. Dry silica was added to a glass filter filled with silica gel (10 × 10 cm). The filter was washed with ethyl acetate, and a 500 mL fraction was collected. Fractions 2-4 contained the title compound. The solvent was evaporated and the residue was crystallized from acetone / hexanes to give the title nucleoside (3.3 g, 72%).

Step 4. 7- (2′-Methyl-β-D-ribofuranosyl) -4-amino-5-iodo-pyrrolo [2,3-d] pyrimidine:
The nucleoside prepared above (1.5 g, 3.5 mmol) was treated with liquid ammonia at 85 ° C. for 24 hours in a metal pressure resistant reactor. After evaporation of ammonia, the residue was dissolved in methanol and coevaporated with silica gel (ca. 20 mL). The silica gel carrying the product was placed on a column (5 × 10 cm) packed with silica gel in acetone and 50 mL fractions were fractionated. Fractions 2-8 contained the title compound. Acetone was evaporated and the residue was crystallized from methanol / acetonitrile to give the title nucleoside (1.2 g, 84%).

Step 5. 7- (2′-Methyl-β-D-ribofuranosyl) -4-amino-5- (trimethylsilanylethyn-1-yl) -pyrrolo [2,3-d] pyrimidine:
The aminonucleoside synthesized in the previous step (1.7 g, 4.2 mmol) was dissolved in a mixture of anhydrous DMF (12 mL) and anhydrous THF (28 mL). Triethylamine (3.6 mmol, 0.5 mL), CuI (1 mmol, 80 mg) were added and the flask was filled with argon. Tetrakis (triphenylphosphine) palladium (0) (0.04 mmol, 46 mg) was added followed by (trimethylsilyl) acetylene and the mixture was stirred under an argon atmosphere for 20 hours.

The solvent was evaporated and the residue in acetone was filtered through silica gel (5 × 10 cm). The acetone was evaporated and the residue was dissolved in acetonitrile and then filtered again through the same size silica gel column. Elution was performed with pure acetonitrile. Acetonitrile was concentrated to a small volume, about 10 times the amount of ether was added, and the solution was sonicated for 5 minutes. White crystals of the title compound were formed (yield 0.8 g, 71%).

実施例2、段階4からの化合物のDMF溶液（0.05M）に1.0当量のTEA、0.4eqのCuI、6.0当量の2-エチニル-ピリジンを加える。この混合物をアルゴンで脱気し、10モル％のP(Ph₃)₄Pdを加え、反応混合物を25〜80℃の間で24時間撹拌する。次いで、反応混合物を減圧濃縮し、DMFに溶解し、PHenominexカラム（250×20mm）によるRP HPLCで、30分間に水中アセトニトリルの0から80％勾配を用い、流速10mL/分で精製する。 Example 3
Preparation of 7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5- [2- (pyrid-2-yl) ethyn-1yl] -pyrrolo [2,3-d] pyrimidine

To a DMF solution (0.05 M) of the compound from Example 2, Step 4, 1.0 eq TEA, 0.4 eq CuI, 6.0 eq 2-ethynyl-pyridine are added. The mixture is degassed with argon, 10 mol% P (Ph ₃ ) ₄ Pd is added and the reaction mixture is stirred between 25-80 ° C. for 24 hours. The reaction mixture is then concentrated under reduced pressure, dissolved in DMF and purified by RP HPLC with a PHenominex column (250 × 20 mm) using a 0 to 80% gradient of acetonitrile in water over 30 minutes at a flow rate of 10 mL / min.

実施例8からの生成物（20mg、0.053mmol）の溶液に、濃アンモニア溶液（30％水溶液、1.0mL）を加え、室温で1時間撹拌した。得られた沈殿をろ過し、エタノールとの共蒸発により乾燥して、標題化合物（15mg、80％）を得た。

Example 4
Preparation of 7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5- (2-carboxamidoethyn-1-yl) -pyrrolo [2,3-d] pyrimidine

To a solution of the product from Example 8 (20 mg, 0.053 mmol) was added concentrated ammonia solution (30% aqueous solution, 1.0 mL) and stirred at room temperature for 1 hour. The resulting precipitate was filtered and dried by co-evaporation with ethanol to give the title compound (15 mg, 80%).

実施例2、段階4からの化合物（100mg、0.246mmol）のTHF-DMF（3：1 v/v、6.5mL）溶液にCuI（18.2mg、0.096mmol）、TEA（32μL、0.23mmol）、プロピオールアルデヒドジエチルアセタール（0.05mL、0.36mmol）を加えた。混合物をアルゴンで脱気し、P(Ph₃)₄Pd（28mg、0.024mmol）を加え、反応混合物を室温で3.5時間撹拌した。プロピオールアルデヒドジエチルアセタールの第二投入量（0.05mL）を加え、反応混合物を室温で一晩撹拌した。次いで、反応混合物を減圧濃縮し、シリカゲル（100％CH₂Cl₂でゲル上にプレーティングし、15％MeOH-CH₂Cl₂で溶出）で精製して、標題化合物（60mg、60％）を得た。

Example 5
Preparation of 7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5- [3,3-diethoxyproparg-1-yl) -pyrrolo [2,3-d] pyrimidine

Example 2, Step 4 compound (100 mg, 0.246 mmol) in THF-DMF (3: 1 v / v, 6.5 mL) in CuI (18.2 mg, 0.096 mmol), TEA (32 μL, 0.23 mmol), propidium. Allaldehyde diethyl acetal (0.05 mL, 0.36 mmol) was added. The mixture was degassed with argon, P (Ph ₃ ) ₄ Pd (28 mg, 0.024 mmol) was added and the reaction mixture was stirred at room temperature for 3.5 hours. A second charge of propiolaldehyde diethyl acetal (0.05 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure, (plated onto the gel in 100% CH ₂ Cl _2, eluted with _{15% MeOH-CH 2 Cl 2} ) on silica gel to give the title compound (60 mg, 60%) Obtained.

実施例2、段階4からの化合物のDMF溶液に1.0当量のTEA、0.4eqのCuI、6.0当量の1-エチニル-4-メトキシ-ベンゼンを加える。この混合物をアルゴンで脱気し、10モル％のP(Ph₃)₄Pdを加え、反応混合物を25〜80℃の間で24時間撹拌する。次いで、反応混合物を減圧濃縮し、DMFに溶解し、PHenominexカラム（250×20mm）によるRP HPLCで、30分間に水中アセトニトリルの0から80％勾配を用い、流速10mL/分で精製する。 Example 6
Preparation of 7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5- [2- (4-methoxyphenyl) ethyn-1-yl] -pyrrolo [2,3-d] dipyrimidine

To the DMF solution of the compound from Example 2, Step 4, 1.0 eq. TEA, 0.4 eq CuI, 6.0 eq 1-ethynyl-4-methoxy-benzene are added. The mixture is degassed with argon, 10 mol% P (Ph ₃ ) ₄ Pd is added and the reaction mixture is stirred between 25-80 ° C. for 24 hours. The reaction mixture is then concentrated under reduced pressure, dissolved in DMF and purified by RP HPLC with a PHenominex column (250 × 20 mm) using a 0 to 80% gradient of acetonitrile in water over 30 minutes at a flow rate of 10 mL / min.

実施例2、段階4からの生成物（50.0mg、0.1231mmol）のジメチルホルムアミド（5mL）溶液を調製した。溶液を超音波処理しながらアルゴンを通気することにより5分間脱気した。この溶液に、トリエチルアミン（16.0μL、0.1145mmol）、ヨウ化銅（9.4mg、0.0492mmol）、およびテトラキス(トリフェニルホスフィン)パラジウム(0)（14.2mg、0.0123mmol）を加えた。次に、フェニルアセチレン（81.1μL、0.7386mmol）を加えた。混合物をアルゴン雰囲気下で4時間撹拌した。完了後、混合物を減圧濃縮した。粗反応物をジメチルホルムアミド（1mL）に溶解し、脱イオン水で50mLに希釈し、次いでセライトパッドを通して洗浄した。溶液を再度濃縮乾固し、次いでジメチルホルムアミド（1.0mL）および水（3.5mL）に再度溶解した。標題化合物をHPLCで精製した。

Example 7
Preparation of 7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5- (2-phenylethyn-1yl) -pyrrolo [2,3-d] pyrimidine

A solution of the product from Example 2, Step 4 (50.0 mg, 0.1231 mmol) in dimethylformamide (5 mL) was prepared. The solution was degassed for 5 minutes by bubbling argon while sonicating. To this solution was added triethylamine (16.0 μL, 0.1145 mmol), copper iodide (9.4 mg, 0.0492 mmol), and tetrakis (triphenylphosphine) palladium (0) (14.2 mg, 0.0123 mmol). Next, phenylacetylene (81.1 μL, 0.7386 mmol) was added. The mixture was stirred for 4 hours under an argon atmosphere. After completion, the mixture was concentrated in vacuo. The crude reaction was dissolved in dimethylformamide (1 mL), diluted to 50 mL with deionized water and then washed through a celite pad. The solution was concentrated again to dryness and then redissolved in dimethylformamide (1.0 mL) and water (3.5 mL). The title compound was purified by HPLC.

実施例2、段階4からの生成物（450.0mg、1.108mmol）のTHF-DMF（2：1 v/v、28.8mL）溶液にCuI（0.082g、0.432mmol）、TEA（144μL、1.035mmol）、テトラキス(トリフェニルホスフィン)パラジウム(0)（0.126g、0.108mmol）を加え、溶液をアルゴンで脱気した。プロピオール酸エチル（100μL、1.011mmol）を加え、反応混合物を55℃に加熱した。プロピオール酸エチル（100μL）を1時間ごとに6時間、TLCにより実施例2、段階4の出発原料がなくなるまで追加した。反応混合物を減圧濃縮し、DMFに溶解し、PHenominexカラム（250×20mm）によるRP HPLCで、30分間に水中アセトニトリルの0から60％勾配を用い、流速10mL/分で精製して、標題化合物（115mg、28％）を得た。

Example 8
Preparation of 7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5- (ethyl 2-carboxylethin-1yl-pyrrolo [2,3-d] pyrimidine

CuI (0.082 g, 0.432 mmol), TEA (144 μL, 1.035 mmol) in a THF-DMF (2: 1 v / v, 28.8 mL) solution of the product from Example 2, Step 4 (450.0 mg, 1.108 mmol) Tetrakis (triphenylphosphine) palladium (0) (0.126 g, 0.108 mmol) was added and the solution was degassed with argon. Ethyl propiolate (100 μL, 1.011 mmol) was added and the reaction mixture was heated to 55 ° C. Ethyl propiolate (100 μL) was added every hour for 6 hours until the starting material from Example 2, Step 4 was gone by TLC. The reaction mixture was concentrated in vacuo, dissolved in DMF and purified by RP HPLC on a PHenominex column (250 × 20 mm) using a 0 to 60% gradient of acetonitrile in water over 30 minutes at a flow rate of 10 mL / min to give the title compound ( 115 mg, 28%).

実施例8からの生成物（20.0mg、0.053mmol）に、1N NaOH（500μL）を加え、室温で30分間撹拌した。次いで、反応混合物を水で希釈し、Phenominexカラム（250×20mm）によるRP HPLCで、30分間に水中アセトニトリルの0から60％勾配を用い、流速10mL/分で精製して、標題化合物（7.0mg、38％）を得た。

Example 9
Preparation of 7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5- (2-carboxylethyn-1yl) -pyrrolo [2,3-d] pyrimidine

To the product from Example 8 (20.0 mg, 0.053 mmol) was added 1N NaOH (500 μL) and stirred at room temperature for 30 minutes. The reaction mixture was then diluted with water and purified by RP HPLC with a Phenominex column (250 × 20 mm) using a 0 to 60% gradient of acetonitrile in water over 30 minutes at a flow rate of 10 mL / min to give the title compound (7.0 mg 38%).

段階1. 7-(2'-C-メチル-β-D-リボフラノシル)-4-アミノ-5-(ホルミル)-ピロロ[2,3-d]ピリミジンの調製：
7-(2'-C-メチル-β-D-リボフラノシル)-4-アミノ-5-(ホルミル)-ピロロ[2,3-d]ピリミジンをShin-ichi Watanabe and Tohru Ueda in Nucleosides and Nucleotides (1983) 2(2), 113-125に記載の方法に従って合成した。しかし、標題化合物の合成において、7-(2'-C-メチル-β-D-リボフラノシル)-4-アミノ-ピロロ[2,3-d]ピリミジン（Carroll, et al.,^11,12参照）をツベルシジンの代わりに用いた。

Example 10
Preparation of 7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5- (2-cis-methoxyethen-1-yl) -pyrrolo [2,3-d] pyrimidine

Step 1. Preparation of 7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (formyl) -pyrrolo [2,3-d] pyrimidine:
7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5- (formyl) -pyrrolo [2,3-d] pyrimidine was converted to Shin-ichi Watanabe and Tohru Ueda in Nucleosides and Nucleotides (1983 ) Synthesized according to the method described in 2 (2), 113-125. However, in the synthesis of the title compound, 7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-pyrrolo [2,3-d] pyrimidine (see Carroll, et al., ^11,12 ) Was used in place of tubercidin.

Step 2. Preparation of the title compound:
The product from Step 1 above (0.050 g, 0.162 mmol) was dissolved in DMSO (2 mL) and added dropwise to the pregenerated ylide of (methoxymethyl) -triphenylphosphonium chloride and stirred at room temperature. The ylide is formed by dissolving (methoxymethyl) -triphenylphosphonium chloride (0.555 g, 1.62 mmol) in DMSO (10 mL) and adding 2M methylsulfinyl carbanion solution (0.81 mL, 1.62 mmol) for 15 minutes at room temperature. Stir. After stirring at room temperature for 4 hours, a second charge (1.62 mmol) of (methoxymethyl) -triphenylphosphonium chloride ylide was added to the reaction mixture and stirred at room temperature overnight. The reaction was quenched with water and diluted with methylene chloride. The layers were separated and the organic layer was extracted twice with water. The aqueous layers were combined and concentrated under reduced pressure and purified by RP HPLC on a Phenominex column (250 x 20 mm) using a 0 to 30% gradient of acetonitrile in water for 30 minutes at a flow rate of 10 mL / min to give trans enol ether (20 mg) And the cis isomer (10 mg) was obtained (56% yield).

実施例2からの標題化合物（0.040g、0.0132mmol）をメタノールに溶解し、NH₄0Hを加え、混合物を周囲温度で1時間放置した。溶媒を蒸発させ、残渣をメタノールに溶解し、シリカゲルと共蒸発させた。乾燥シリカゲルをシリカゲルを充填したガラスフィルターに加え、脱シリル化化合物をアセトンで溶出した。溶媒を蒸発させ、残渣をメタノール/アセトニトリルから結晶化して、7-(2'-C-メチル-β-D-リボフラノシル)-4-アミノ-5-(エチン-1-イル)-ピロロ[2,3-d]ピリミジンを得た。

Example 11
Preparation of 7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5- (ethen-1-yl) -pyrrolo [2,3-d] pyrimidine

The title compound from Example 2 (0.040 g, 0.0132 mmol) was dissolved in methanol, NH ₄ 0H was added and the mixture was left at ambient temperature for 1 hour. The solvent was evaporated and the residue was dissolved in methanol and coevaporated with silica gel. Dry silica gel was added to a glass filter filled with silica gel, and the desilylated compound was eluted with acetone. The solvent was evaporated and the residue was crystallized from methanol / acetonitrile to give 7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (ethyn-1-yl) -pyrrolo [2, 3-d] pyrimidine was obtained.

The acetylene product prepared above was dissolved in THF (3 mL) and Lindlar catalyst (22 mg) was added. The solution was stirred at ambient temperature under 1 atm hydrogen atmosphere (balloon) for 7 days. The balloon was refilled with hydrogen at the beginning of each day. After 7 days, the reaction mixture was filtered through celite to remove the catalyst, concentrated under reduced pressure, and reverse phase HPLC on a Phenominex column (250 x 20 mm) using a 0 to 30% gradient of acetonitrile in water over 30 minutes at a flow rate of 10 mL / Purification in minutes gave the title compound (30 mg, 75% yield).

段階1. 4-クロロ-5-ヨード-7H-ピロロ[2,3-d]ピリミジン：
4-クロロ-7H-ピロロ[2,3-d]ピリミジン（10.75g、70mmol）およびN-ヨードスクシンイミド（16.8g、75mmol）を無水DMF（400mL）に溶解し、周囲温度で暗所に一晩放置した。溶媒を蒸発させた。黄色残渣をNa₂SO₃の10％熱溶液に懸濁し、ろ過し、熱水で二回洗浄し、エタノールから結晶化して、標題化合物（14.6g、74.6％）をオフホワイト結晶で得た。母液を1/3量まで蒸発させ、エタノールから再度結晶化して、標題生成物（2.47g、12.3％）を得た。

Example 12
Preparation of 7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5- (formyl) -pyrrolo [2,3-d] pyrimidine

Step 1. 4-Chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine:
4-Chloro-7H-pyrrolo [2,3-d] pyrimidine (10.75 g, 70 mmol) and N-iodosuccinimide (16.8 g, 75 mmol) are dissolved in anhydrous DMF (400 mL) and overnight in the dark at ambient temperature. I left it alone. The solvent was evaporated. The yellow residue was suspended in a 10% hot solution of Na ₂ SO ₃ , filtered, washed twice with hot water and crystallized from ethanol to give the title compound (14.6 g, 74.6%) as off-white crystals. The mother liquor was evaporated to 1/3 volume and recrystallized from ethanol to give the title product (2.47 g, 12.3%).

Step 2. 7- (2'-Methyl-3 ', 5'-bis-O- (2,4-dichlorobenzyl-β-D-ribofuranosyl) -4-chloro-5-iodo-pyrrolo [2,3- d] Pyrimidine:
The base obtained as described above (11.2 g, 40 mmol) was suspended in CH ₃ CN (500 mL), NaH (1.6 g, 40 mmol, 60% in oil) was added and the reaction mixture was dissolved at room temperature until the NaH was dissolved ( Stir for about 2 hours. 1-O-methyl-2-methyl-3,5-bis-O- (2,4-dichlorobenzyl) -β-D-ribofuranose (10 g, 20 mmol) is dissolved in DCM (500 mL) and ice / water bath Cooled to 4 ° C. HBr-gas was bubbled through the DCM solution for about 30 minutes. The reaction was controlled by TLC by disappearance of the starting sugar (ether / hexane 1: 9 v / v). After the reaction was complete, the solvent was evaporated at a temperature below 20 ° C. and maintained under high vacuum for 20 minutes to remove traces of HBr. The base Na salt solution was rapidly filtered and the filtrate was added to the sugar component. The reaction was continued overnight at ambient temperature, neutralized with 0.1 NH ₂ SO ₄ and evaporated. The residue was partitioned between ethyl acetate (700 mL) and water (700 mL). The organic fraction was washed with water (150 mL), brine (150 mL), dried over Na ₂ SO ₄ and evaporated to give a semi-crystalline mixture. Toluene (500 mL) was added to give a pale tan precipitate (2.5 g, 25%) of unreacted heterocyclic base. The filtrate was concentrated to a volume of 50 mL and added to a glass filter packed with silica gel (10 × 10 cm). The filter was washed with 10% ethyl acetate in toluene and a 500 mL fraction was collected. Fractions 2-4 contained the title compound and fractions 6-7 contained heterocyclic bases.

Fractions 2-4 were evaporated, ether was added to the colorless oil and the mixture was sonicated for 5 minutes. An off-white precipitate was formed (yield 7.4 g, 50%). The mother liquor was evaporated and the above procedure was repeated to give an additional 0.7 g of the title nucleoside. The total yield is 8.1 g (54.4%).

Step 3. 7- (2′-Methyl-β-D-ribofuranosyl) -4-chloro-5-iodo-pyrrolo [2,3-d] pyrimidine:
A solution of the compound from the previous step (8 g, 10.7 mmol) in DCM (200 mL) was cooled to −78 ° C., and boron trichloride (1 M in DCM, 88 mL, 88 mmol) was added dropwise thereto. The mixture was stirred at −78 ° C. for 2.5 hours and at −20 ° C. overnight. Methanol / DCM (90 mL, 1: 1) was added to quench the reaction, and the resulting mixture was stirred at −20 ° C. for 30 minutes and then neutralized with aqueous ammonia at the same temperature. The solid was filtered and washed with methanol / DCM (250 mL, 1: 1). The filtrate was mixed with silica gel (50 mL) and evaporated to dryness. Dry silica was added to a glass filter filled with silica gel (10 × 10 cm). The filter was washed with ethyl acetate, and a 500 mL fraction was collected. Fractions 2-4 contained the title compound. The solvent was evaporated and the residue was crystallized from acetone / hexanes to give the title nucleoside (3.3 g, 72%).

Step 4. 7- (2′-Methyl-β-D-ribofuranosyl) -4-amino-5-iodo-pyrrolo [2,3-d] pyrimidine:
The nucleoside prepared above (1.5 g, 3.5 mmol) was treated with liquid ammonia at 85 ° C. for 24 hours in a metal pressure resistant reactor. After evaporation of ammonia, the residue was dissolved in methanol and coevaporated with silica gel (ca. 20 mL). The silica gel carrying the product was placed on a column (5 × 10 cm) packed with silica gel in acetone and 50 mL fractions were fractionated. Fractions 2-8 contained the title compound. Acetone was evaporated and the residue was crystallized from methanol / acetonitrile to give the title nucleoside (1.2 g, 84%).

Step 5. Preparation of the title compound:
A solution of the compound prepared in Step 4 above (50.0 mg, 0.1231 mmol) in anhydrous tetrahydrofuran (5 mL) was prepared, and then air was removed by slowly bubbling carbon monoxide through it. To this solution was added tetrakis (triphenylphosphine) palladium (0) (2.8 mg, 0.0025 mmol). The reaction mixture was stirred for 10 minutes and then heated to 50 ° C. Next, tributyltin hydride in THF (35.9 μL, 0.1354 mmol) was added slowly over 2.5 hours, during which time CO gas was continuously bubbled. After completion, the mixture was concentrated in vacuo. The crude reaction was dissolved in dimethylformamide (1 mL), diluted to 50 mL with deionized water and then washed through a celite pad. The solution was concentrated again to dryness and then redissolved in dimethylformamide (1.0 mL) and water (3.5 mL). The title compound was purified by HPLC.

50％エタノール（10mL）中の実施例12からの標題化合物（0.1g、0.325mmol）の溶液に、塩酸ヒドロキシルアミン（0.073g、1.05mmol）およびKOAc（0.103g、1.05mmol）を加え、60℃で2.5時間加熱した。粗製混合物を濃縮し、水で希釈し、Phenominexカラム（250×20mm）による逆相HPLCで、30分間に水中アセトニトリルの0から30％勾配を用い、流速10mL/分で精製して、標題化合物（10mg）を得た。

Example 13
Preparation of 7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5- (carbaldehyde oxime) -pyrrolo [2,3-d] pyrimidine

To a solution of the title compound from Example 12 (0.1 g, 0.325 mmol) in 50% ethanol (10 mL) was added hydroxylamine hydrochloride (0.073 g, 1.05 mmol) and KOAc (0.103 g, 1.05 mmol) at 60 ° C. For 2.5 hours. The crude mixture was concentrated, diluted with water and purified by reverse phase HPLC on a Phenominex column (250 × 20 mm) using a 0-30% gradient of acetonitrile in water over 30 minutes at a flow rate of 10 mL / min to give the title compound ( 10 mg) was obtained.

DMSO（1mL）中の実施例2、段階4からの化合物（60mg、0.148mmol）の溶液に、KOAc（44mg、0.449mmol）、ビス(ネオペンチルグリコロト)ジボロン（40mg、0.177mmol）を加えた。混合物をアルゴンで脱気し、P(Ph₃)₂PdCl₂（3.1mg、0.004mmol）を加え、反応混合物を80℃で4時間加熱した。混合物を水で希釈し、Phenominexカラム（250×20mm）によるRP HPLCで、30分間に水中アセトニトリルの0から50％勾配を用い、流速10mL/分で精製して、標題化合物（16mg、33％）を得た。

Example 14
Preparation of 7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5- (boronic acid) -pyrrolo [2,3-d] pyrimidine

To a solution of the compound from Example 2, Step 4 (60 mg, 0.148 mmol) in DMSO (1 mL) was added KOAc (44 mg, 0.449 mmol), bis (neopentylglycoloto) diboron (40 mg, 0.177 mmol). . The mixture was degassed with argon, P (Ph ₃ ) ₂ PdCl ₂ (3.1 mg, 0.004 mmol) was added and the reaction mixture was heated at 80 ° C. for 4 h. The mixture was diluted with water and purified by RP HPLC with a Phenominex column (250 × 20 mm) using a 0 to 50% gradient of acetonitrile in water over 30 minutes at a flow rate of 10 mL / min to give the title compound (16 mg, 33%) Got.

無水イソプロパノール中の実施例13、段階5からの化合物の溶液に、活性化モレキュラーシーブスを加え、溶液をHClで酸性化する。溶液を50〜80℃の間で出発原料が消費されてしまうまで加熱する。得られたジアセタールをPhenominexカラム（250×20mm）によるRP HPLCで、30分間に水中アセトニトリルの0から50％勾配を用い、流速10mL/分で精製する。 Example 15
Preparation of 7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5- (diisopropoxymethyl) -pyrrolo [2,3-d] pyrimidine

To a solution of the compound from Example 13, Step 5 in anhydrous isopropanol is added activated molecular sieves and the solution is acidified with HCl. The solution is heated between 50-80 ° C. until the starting material has been consumed. The resulting diacetal is purified by RP HPLC with a Phenominex column (250 × 20 mm) using a 0-50% gradient of acetonitrile in water for 30 minutes at a flow rate of 10 mL / min.

DMF中の実施例12、段階5からの化合物（20mg、0.05mmol）の溶液に、ヒドラジン（2μL、0.060mmol）を加え、50℃で2.5時間撹拌した。粗反応物をPhenominexカラム（250×20mm）によるRP HPLCで、30分間に水中アセトニトリルの0から50％勾配を用い、流速10mL/分で直接精製して、標題化合物（12mg、75％）を得た。

Example 16
Preparation of 7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5- (hydrazono) -pyrrolo [2,3-d] pyrimidine

To a solution of the compound from Example 12, Step 5 (20 mg, 0.05 mmol) in DMF was added hydrazine (2 μL, 0.060 mmol) and stirred at 50 ° C. for 2.5 hours. The crude reaction was directly purified by RP HPLC with a Phenominex column (250 x 20 mm) using a 0 to 50% gradient of acetonitrile in water for 30 minutes at a flow rate of 10 mL / min to give the title compound (12 mg, 75%). It was.

Example 17
Synthesis of 7- (2'-methyl-β-D-ribofuranosyl) -4-amino-5- (2-phenylethyn-1-yl) -pyrrolo [2,3-d] pyrimidine 5'-triphosphate
7- (2′-Methyl-β-D-ribofuranosyl) -4-amino-5- (2-phenylethyn-1-yl) -pyrrolo [2,3-d] pyrimidine 5′-triphosphate (0.1 mmol ) Is co-evaporated three times with anhydrous DMF, dissolved in PO (OMe) ₃ (2 mL), cooled to 5 ° C., and POCl ₃ (35 μL) and proton sponge (64 mg) are added. The mixture is stirred at 5 ° C. for 3 hours, tetrabutylammonium pyrophosphate (2 mmol, 4 mL of 0.5 M DMF solution) is added and the mixture is maintained at the same temperature for a further 2 hours. The reaction is quenched with (Et ₃ N) HCO ₃ buffer (pH 7.5) followed by water. The solvent is evaporated and the residue is dissolved in methanol (3 mL) and precipitated with ether (30 mL). The solid residue is purified by ion exchange HPLC on a Vydac column (250 × 10 mm), 0 to 100% B. Buffer A is 25 mM NaH ₂ PO ₄ / Na ₂ HPO ₄ , pH 3, and buffer B is 310 mM NaH ₂ PO ₄ / Na ₂ HPO ₄ , pH 3. The last peak is collected, concentrated to a volume of 5 mL, and purified again with a 0 to 100% gradient of buffer B in buffer A by RP HPLC with a Phenominex column (250 × 20 mm). Buffer A is a 0.5 M triethylammonium acetate aqueous solution, and buffer B is a 0.5 M triethylammonium acetate in acetonitrile solution. Fractions containing the title compound are combined, evaporated, co-evaporated three times with water and lyophilized from water.

Example 18
Synthesis of 7- (2'-methyl-β-D-ribofuranosyl) -4-amino-5- (2-phenylethyn-1-yl) -pyrrolo [2,3-d] pyrimidine 5'-phosphate
7- (2'-Methyl-β-D-ribofuranosyl) -4-amino-5- (2-phenylethyn-1-yl) -pyrrolo [2,3-d] pyrimidine (0.1 mmol) was mixed with anhydrous DMF and Co-evaporate, dissolve in PO (OMe) ₃ (2 mL), cool to 5 ° C. and add POCl ₃ (35 μL) and proton sponge (64 mg). The mixture is stirred at 5 ° C. for 3 hours. The reaction is quenched with (Et ₃ N) HCO ₃ buffer (pH 7.5) followed by water. The solvent is evaporated and the residue is dissolved in methanol (3 mL) and precipitated with ether (30 mL). The solid residue is purified by ion exchange HPLC on a Vydac column (250 × 10 mm), 0 to 100% B. Buffer A is 25 mM NaH ₂ PO ₄ / Na ₂ HPO ₄ , pH 3, and buffer B is 310 mM NaH ₂ PO ₄ / Na ₂ HPO ₄ , pH 3. The last peak is collected, concentrated to a volume of 5 mL, and purified again with a 0 to 100% gradient of buffer B in buffer A by RP HPLC with a Phenominex column (250 × 20 mm). Buffer A is a 0.5 M triethylammonium acetate aqueous solution, and buffer B is a 0.5 M triethylammonium acetate in acetonitrile solution. Fractions containing the title compound are combined, evaporated, co-evaporated three times with water and lyophilized from water.

Biological examples
Example 1. Anti-hepatitis C virus active compounds can inhibit HCV polymerase, inhibit other enzymes required for the replication cycle, or exhibit anti-hepatitis C virus activity by other pathways. Several assays have been reported to assess these activities. A general method for assessing the total increase in HCV virus in culture is disclosed in US Pat. No. 5,738,985 to Miles et al. In vitro assays are described in Ferrari et al. Jnl. Of Vir., 73: 1649-1654, 1999; Ishii et al., Hepatology, 29: 1227-1235, 1999; Lohmann et al., Jnl of Bio. Chem., 274: 10807-10815, 1999; and Yamashita et al., Jnl. Of Bio. Chem., 273: 15479-15486, 1998.

  International Publication No. 97/12033 filed Sep. 27, 1996 by Emory University, listing C. Hagedorn and A. Reinoldus as inventors, US Provisional Patent Application No. 60 / 004,383 filed Sep. 1995. HCV polymerase assay is described which can be used to assess the activity of the compounds described herein. Another HCV polymerase assay is reported by Barthholomeusz, et al., Hepatitis C Virus (HCV) RNA polymerase assay using cloned HCV non-structural proteins; Antiviral Therapy 1996: 1 (Supp 4) 18-24.

  Selection methods for measuring the reduction of kinase activity from HCV drugs are disclosed in Katze et al., U.S. Patent No. 6,030,785, Delvecchio, U.S. Patent No. 6,228,576, and Jubin et al., U.S. Patent No. 5,759,795. . Screening methods for measuring the protease inhibitory activity of recommended HCV drugs are disclosed in US Pat. No. 5,861,267 to Su et al., US Pat. No. 5,739,002 to De Francesco et al., And US Pat. No. 5,597,691 to Houghton et al. Has been.

Example 2. Replicon assay
The cell line ET (Huh-lucubineo-ET) is used to screen the compounds of the invention for HCV RNA-dependent RNA polymerase. The ET cell line is EMCV-IRES-driven containing I ₃₈₉ luc-ubi-neo / NS3-3 '/ ET; firefly luciferase-ubiquitin-neomycin phosphotransferase fusion protein and cell culture adaptive mutation (E1202G; T1280I; K1846T) RNA transcripts with NS3-5B polyprotein have been stably transfected (Krieger at al, 2001 and unpublished). ET cells are cultured in DMEM supplemented with 10% fetal calf serum, 2 mM glutamine, penicillin (100 IU / mL) / streptomycin (100 μg / mL), 1 × nonessential amino acids, and 250 μg / mL G418 (geneticin). All of these are available from Life Technologies (Bethesda, MD). Cells are seeded in 96-well plates at 0.5-1.0 × 10 ⁴ cells / well and incubated for 24 hours before the nucleoside analog is added. Compound cells were then added to a final concentration of 50 or 100 μM, or any other concentration desired. For these evaluations, 6 dilutions of each compound are used. Compounds are typically diluted 3-fold to expand to a 250-fold concentration range. Luciferase activity is measured 48-72 hours later by adding lysis buffer and substrate (Catalog Number Glo-lysis buffer E2661 and Bright-Glo luciferase system E2620 Promega, Madison, Wis.). Cells should not become too confluent during the assay. Percent inhibition of replication is plotted against a control without compound. Under the same conditions, the cytotoxicity of the compounds is evaluated using the cell proliferation reagent WST-1 (Roche, Germany). IC ₅₀ and TC ₅₀ values are calculated by substituting% inhibition at each concentration into the following formula (b is Hill coefficient).
% Inhibition = 100% / [(IC ₅₀ / [I]) ^b +1]

Example 3. Cloning and expression of recombinant HCV-NS5b
The NS5b protein coding sequence is cloned by PCR from pFKI ₃₈₉ luc / NS3-3 '/ ET using the following primers as described in Lohmann, V., et al. (1999) Science 285, 110-113 :

  The cloned fragment lacks the C-terminal 21 amino acid residues. The cloned fragment is inserted into an IPTG inducible expression plasmid that provides an epitope tag (His) 6 at the carboxy terminus of the protein.

  Recombinant enzyme is expressed in XL-1 cells, and after induction of expression, the protein is purified using affinity chromatography on a nickel-NTA column. The storage conditions are 10 mM Tris-HCl pH 7.5, 50 mM NaCl, 0.1 mM EDTA, 1 mM DTT, 20% glycerol at −20 ° C.

Example 4. HCV-NS5b Enzyme Assay Polymerase activity is assessed by measuring the incorporation of radioisotope-labeled UTP into the RNA product using a biotinylated heteropolymer template containing a portion of the HCV genome. Typically, the assay mixture (50 μL) is 10 mM Tris-HCl (pH 7.5), 5 mM MgCl ₂ , 0.2 mM EDTA, 10 mM KCl, 1 unit / μL RNAsin, 1 mM DTT, 10 μM [ ³ H] -UTP each. Including NTP and 10 ng / μL heteropolymer template. Test compounds are first dissolved in 100% DMSO and further diluted with an aqueous buffer containing 5% DMSO. Typically, compounds are tested at concentrations from 1 nM to 100 μM. Start the reaction by adding enzyme and continue for 2 hours at 37 ° C. Stop the reaction with 8 μL of 100 mM EDTA, transfer the reaction mixture (30 μL) to a streptavidin-coated scintillation proximity microtiter plate (FlashPlate) and incubate overnight at 4 ° C. Radioactivity uptake is assessed by scintillation counting.

  Table II below shows the results of the replicon assay or enzyme assay used to test the compounds of the present invention.

Formulation Examples The following are representative pharmaceutical formulations containing a compound of the present invention.

Example 1: Tablet formulation The following ingredients are intimately mixed and compressed into a single groove tablet.

Example 2: Capsule formulation The following ingredients are intimately mixed and filled into hard gelatin capsules.

Example 3: Suspension preparation A suspension for oral administration is prepared by mixing the following ingredients.

Example 4: Injectable preparation An injectable preparation is prepared by mixing the following ingredients.

Example 5: Suppository Formulation A suppository with a total weight of 2.5 g is mixed with a compound of the invention with Witepsol® H-15 (triglycerides of saturated vegetable fatty acids; Riches-Nelson, Inc., New York). And has the following composition:

Claims (50)

Compounds of formula I:

(In the formula
Y is selected from the group consisting of a bond, —CH ₂ — or —O—;
W, W ¹ and W ² are each independently selected from the group consisting of hydrogen and a pharmaceutically acceptable prodrug; and
T is selected from the group consisting of
a) -C≡CR (R is selected from the group consisting of
i) tri (C ₁ ~C ₄₎ ^{alkylsilyl, -C (O) NR 1 R} 2, alkoxyalkyl, heteroaryl, and substituted heteroaryl, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, Alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, aminoacyl, amidino, amino, substituted amino, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, guanidino, halo, heteroaryl, substituted hetero Phenyl substituted with 1 to 3 substituents selected from the group consisting of aryl, hydrazino, hydroxyl, nitro, thiol, and —S (O) _m R ³ ;
Where R ¹ and R ² are hydrogen, alkyl, substituted alkyl, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted, provided that only one of R ¹ and R ² is amino or substituted amino Independently selected from the group consisting of heteroaryl, heterocycle and substituted heterocycle, and R ¹ and R ² together with the nitrogen atom bonded to them form a heterocycle or substituted heterocycle;
R ³ is selected from the group consisting of alkyl, substituted alkyl, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle;
m is an integer of 0, 1 or 2;
ii) -C (O) OR ¹⁴ (R ¹⁴ is hydrogen, alkyl or substituted alkyl));
b) -CH = CH-Q ² (Q ² is selected from hydrogen or cis-methoxy);
c) -C (O) H;
d) -CH = NNHR ¹⁵ (R ¹⁵ is H or alkyl);
e) —CH═N (OR ¹⁵ ) (R ¹⁵ is as defined above);
f) —CH (OR ¹⁶ ) ₂ (R ¹⁶ is (C ₃ -C ₆ ) alkyl) and
g) -B (OR ¹⁵ ) ₂ (R ¹⁵ is as described above));
And pharmaceutically acceptable salts or partial salts thereof. W, W ¹ and W ² are each independently hydrogen or acyl, oxyacyl, phosphonate, phosphate ester, phosphate, phosphonamidate, phosphorodiamidate, phosphoramidate monoester, cyclic phosphoramidate, cyclic Phosphorodiamidate, phosphoramidate diester, and -C (O) CHR ³⁰ NH ₂ (R ³⁰ is composed of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and amino acid side chains 2. The compound of claim 1, which is a pharmaceutically acceptable prodrug selected from the group consisting of:   The compound according to claim 2, wherein W is H. The compound according to claim 2, wherein W ¹ is H. The compound according to claim 2, wherein W ² is H. The compound according to claim 2, wherein W and W ¹ are H. The compound according to claim 2, wherein W and W ² are H. The compound according to claim 2, wherein W ¹ and W ² are H. The compound according to claim ² , wherein W, W ¹ and W ² are H. W ¹ and W ² are hydrogen and W is the following formula:

Wherein R ³⁰ is as defined above, R ⁸ is hydrogen or alkyl, and R ¹⁰ is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted hetero 3. The compound according to claim 2, wherein the compound is selected from the group consisting of aryl, heterocycle and substituted heterocycle. W and W ² is hydrogen and W ¹ is the following formula:

3. The compound according to claim 2, wherein R ³⁰ is as defined above. T is —C≡CR and R is tri (C ₁ -C ₄ ) alkylsilyl, —C (O) NR ¹ R ² , alkoxyalkyl, heteroaryl, substituted heteroaryl, phenyl, and alkyl, substituted alkyl , Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, aminoacyl, amidino, amino, substituted amino, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cyclo From phenyl substituted with 1 to 3 substituents selected from the group consisting of alkoxy, guanidino, halo, heteroaryl, substituted heteroaryl, hydrazino, hydroxyl, nitro, thiol, and —S (O) _m R ³ Selected from the group consisting of;
Where R ¹ and R ² are hydrogen, alkyl, substituted alkyl, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted, provided that only one of R ¹ and R ² is amino or substituted amino Independently selected from the group consisting of heteroaryl, heterocycle and substituted heterocycle, and R ¹ and R ² together with the nitrogen atom bonded to them form a heterocycle or substituted heterocycle;
R ³ is selected from the group consisting of alkyl, substituted alkyl, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle;
The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein m is an integer of 0, 1 or 2. R is _{-C (O) NH 2, -Si} (CH 3) 3, pyrid-2-yl, 4-methoxyphenyl, and -CH (OCH ₂ CH ₃₎ is selected from the group consisting of _2, claim 12 The described compound.   The compound according to any one of claims 1 to 11, wherein T is -C≡C-R and R is -C (O) OH. The compound according to any one of claims 1 to 11, wherein T is -C≡CR, R is -C (O) OR ¹⁴ and R ¹⁴ is alkyl. R ¹⁴ is methyl or ethyl compound according to claim 15, wherein. T is ^{-CH = CH-Q 2 (Q} 2 is selected from hydrogen or cis- methoxy) The compound of any one of claims 1 11.   The compound according to any one of claims 1 to 11, wherein T is -C (= O) H. The compound according to any one of claims 1 to 11, wherein T is -CH = NNHR ¹⁵ (R ¹⁵ is independently selected from the group consisting of hydrogen and alkyl). T is ^{-CH = N (OR 15) (} R 15 is independently selected from the group consisting of hydrogen and alkyl), compounds of any one of claims 1 11. T is _{^{-CH (OR 16) 2 (R}} 16 is independently (C ₃ -C ₆₎ alkyl), compounds of any one of claims 1 11. T is a _{^{-B (OR 15) 2 (R}} 15 is independently selected from the group consisting of hydrogen and alkyl), compounds of any one of claims 1 11. A compound selected from the group consisting of:
7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (2′-trimethylsilylethyn-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- [2- (pyrid-2-yl) ethyn-1-yl] -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- [2- (pyrid-4-yl) ethyn-1-yl] -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (2- (4-methoxyphenyl) -ethyn-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (2-carboxamidoethyn-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5-[(3,3-diethoxy) proparg-1-yl] -pyrrolo [2,3-d] pyrimidine;
7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5-[(N, N-dimethyl-2-carboxamido) ethyn-1-yl] -pyrrolo [2,3-d] Pyrimidine;
7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5-[(N-amino-2-carboxamido) ethyn-1-yl] -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-phospho-β-D-ribofuranosyl) -4-amino-5- (2′-trimethylsilylethyn-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-phospho-β-D-ribofuranosyl) -4-amino-5- [2- (pyrid-2-yl) ethyn-1-yl] -pyrrolo [2,3 -d] pyrimidine;
7- (2′-C-methyl-5′-phospho-β-D-ribofuranosyl) -4-amino-5- [2- (pyrid-4-yl) ethyn-1-yl] -pyrrolo [2,3 -d] pyrimidine;
7- (2′-C-methyl-5′-phospho-β-D-ribofuranosyl) -4-amino-5- (2- (4-methoxyphenyl) ethyn-1-yl) -pyrrolo [2,3- d] pyrimidine;
7- (2′-C-methyl-5′-phospho-β-D-ribofuranosyl) -4-amino-5- (2-carboxamidoethyn-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-phospho-β-D-ribofuranosyl) -4-amino-5-[(3,3-diethoxy) proparg-1-yl] -pyrrolo [2,3-d ] Pyrimidine;
7- (2'-C-methyl-5'-phospho-β-D-ribofuranosyl) -4-amino-5- [2- (N, N-dimethylcarboxamido) ethyn-1-yl] -pyrrolo [2, 3-d] pyrimidine;
7- (2′-C-methyl-5′-phospho-β-D-ribofuranosyl) -4-amino-5- [2- (N-aminocarboxamido) ethyn-1-yl] -pyrrolo [2,3- d] pyrimidine;
7- (2′-C-methyl-5′-diphospho-β-D-ribofuranosyl) -4-amino-5- (2′-trimethylsilylethyn-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-diphospho-β-D-ribofuranosyl) -4-amino-5- [2- (pyrid-2-yl) ethyn-1-yl] -pyrrolo [2,3 -d] pyrimidine;
7- (2'-C-methyl-5'-diphospho-β-D-ribofuranosyl) -4-amino-5- [2- (pyrid-4-yl) ethyn-1-yl] -pyrrolo [2,3 -d] pyrimidine;
7- (2′-C-methyl-5′-diphospho-β-D-ribofuranosyl) -4-amino-5- (2- (4-methoxyphenyl) ethyn-1-yl) -pyrrolo [2,3- d] pyrimidine;
7- (2′-C-methyl-5′-diphospho-β-D-ribofuranosyl) -4-amino-5- (2-carboxamidoethyn-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-diphospho-β-D-ribofuranosyl) -4-amino-5-[(3,3-diethoxy) proparg-1-yl] -pyrrolo [2,3-d ] Pyrimidine;
7- (2'-C-methyl-5'-diphospho-β-D-ribofuranosyl) -4-amino-5-[(N, N-dimethyl-2-carboxamido) ethyn-1-yl] -pyrrolo [2 , 3-d] pyrimidine;
7- (2'-C-methyl-5'-diphospho-β-D-ribofuranosyl) -4-amino-5-[(N-amino-2-carboxamido) ethyn-1-yl] -pyrrolo [2,3 -d] pyrimidine;
7- (2′-C-methyl-5′-triphospho-β-D-ribofuranosyl) -4-amino-5- (2′-trimethylsilylethyn-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2'-C-methyl-5'-triphospho-β-D-ribofuranosyl) -4-amino-5- [2- (pyrid-2-yl) ethyn-1-yl) -pyrrolo [2,3 -d] pyrimidine;
7- (2'-C-methyl-5'-triphospho-β-D-ribofuranosyl) -4-amino-5- [2- (pyrid-4-yl) ethyn-1-yl) -pyrrolo [2,3 -d] pyrimidine;
7- (2'-C-methyl-5'-triphospho-β-D-ribofuranosyl) -4-amino-5- (2- (4-methoxyphenyl) ethyn-1-yl) -pyrrolo [2,3- d] pyrimidine;
7- (2′-C-methyl-5′-triphospho-β-D-ribofuranosyl) -4-amino-5- (2-carboxamidoethyn-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-triphospho-β-D-ribofuranosyl) -4-amino-5-[(3,3-diethoxy) proparg-1-yl] -pyrrolo [2,3-d ] Pyrimidine;
7- (2′-C-Methyl-5′-triphospho-β-D-ribofuranosyl) -4-amino-5-[(N, N-dimethylcarboxylamido) ethyn-1-yl] -pyrrolo [2,3 -d] pyrimidine; and
7- (2'-C-methyl-5'-triphospho-β-D-ribofuranosyl) -4-amino-5-[(N-aminocarboxylamido) ethyn-1-yl] -pyrrolo [2,3-d ] Pyrimidine;
7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (2-carboxyethin-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-phospho-β-D-ribofuranosyl) -4-amino-5- (2-carboxyethyn-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-diphospho-β-D-ribofuranosyl) -4-amino-5- (2-carboxyethin-1-yl) -pyrrolo [2,3-d] pyrimidine; and
7- (2′-C-methyl-5′-triphospho-β-D-ribofuranosyl) -4-amino-5- (2-carboxyethin-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5-[(ethyl 2-carboxyl) ethyn-1-yl] -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5-[(methyl-2-carboxyl) ethyn-1-yl] -pyrrolo [2,3-d] pyrimidine;
7- (2'-C-methyl-5'-phospho-β-D-ribofuranosyl) -4-amino-5-[(ethyl 2-carboxyl) ethyn-1-yl] -pyrrolo [2,3-d] Pyrimidine;
7- (2'-C-Methyl-5'-phospho-β-D-ribofuranosyl) -4-amino-5-[(methyl 2-carboxyl) ethyn-1-yl] -pyrrolo [2,3-d] Pyrimidine;
7- (2′-C-methyl-5′-diphospho-β-D-ribofuranosyl) -4-amino-5-[(ethyl 2-carboxyl) ethyn-1-yl] -pyrrolo [2,3-d] Pyrimidine;
7- (2'-C-methyl-5'-diphospho-β-D-ribofuranosyl) -4-amino-5-[(methyl-2-carboxyl) ethyn-1-yl] -pyrrolo [2,3-d] Pyrimidine;
7- (2'-C-Methyl-5'-triphospho-β-D-ribofuranosyl) -4-amino-5-[(ethyl 2-carboxyl) ethyn-1-yl] -pyrrolo [2,3-d] Pyrimidine;
7- (2'-C-Methyl-5'-triphospho-β-D-ribofuranosyl) -4-amino-5-[(methyl 2-carboxyl) ethyn-1-yl] -pyrrolo [2,3-d] Pyrimidine;
7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (2-phenylethyn-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (2- (4-fluorophenyl) ethyn-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (2- (4-methylphenyl) ethyn-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-phospho-β-D-ribofuranosyl) -4-amino-5- (2-phenylethyn-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2'-C-methyl-5'-phospho-β-D-ribofuranosyl) -4-amino-5- (2- (4-fluorophenyl) ethyn-1-yl) -pyrrolo [2,3- d] pyrimidine;
7- (2'-C-methyl-5'-phospho-β-D-ribofuranosyl) -4-amino-5- (2- (4-methylphenyl) ethyn-1-yl) -pyrrolo [2,3- d] pyrimidine;
7- (2′-C-methyl-5′-diphospho-β-D-ribofuranosyl) -4-amino-5- (2-phenylethyn-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2'-C-methyl-5'-diphospho-β-D-ribofuranosyl) -4-amino-5- (2- (4-fluorophenyl) ethyn-1-yl) -pyrrolo [2,3- d] pyrimidine;
7- (2'-C-methyl-5'-diphospho-β-D-ribofuranosyl) -4-amino-5- (2- (4-methylphenyl) ethyn-1-yl) -pyrrolo [2,3- d] pyrimidine;
7- (2'-C-methyl-5'-triphospho-β-D-ribofuranosyl) -4-amino-5- (2- (4-fluorophenyl) ethyn-1-yl) -pyrrolo [2,3- d] pyrimidine; and
7- (2'-C-methyl-5'-triphospho-β-D-ribofuranosyl) -4-amino-5- (2- (4-methylphenyl) ethyn-1-yl) -pyrrolo [2,3- d] pyrimidine;
7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (ethen-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (2-cis-methoxy-ethen-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-monophospho-β-D-ribofuranosyl) -4-amino-5- (ethen-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-monophospho-β-D-ribofuranosyl) -4-amino-5- (2-cis-methoxy-ethen-1-yl) -pyrrolo [2,3-d] Pyrimidine;
7- (2′-C-methyl-5′-diphospho-β-D-ribofuranosyl) -4-amino-5- (ethen-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2'-C-methyl-5'-diphospho-β-D-ribofuranosyl) -4-amino-5- (2-cis-methoxy-ethen-1-yl) -pyrrolo [2,3-d] Pyrimidine;
7- (2′-C-methyl-5′-triphospho-β-D-ribofuranosyl) -4-amino-5- (ethen-1-yl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-triphospho-β-D-ribofuranosyl) -4-amino-5- (2-cis-methoxy-ethen-1-yl) -pyrrolo [2,3-d] Pyrimidine;
7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (formyl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-phospho-β-D-ribofuranosyl) -4-amino-5- (formyl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-diphospho-β-D-ribofuranosyl) -4-amino-5- (formyl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-triphospho-β-D-ribofuranosyl) -4-amino-5- (formyl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-methyl-β-D-ribofuranosyl) -4-amino-5- (hydrazono) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-phospho-β-D-ribofuranosyl) -4-amino-5- (hydrazono) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-diphospho-β-D-ribofuranosyl) -4-amino-5- (hydrazono) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-triphospho-β-D-ribofuranosyl) -4-amino-5- (hydrazono) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (carbaldehyde oxime) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-phospho-β-D-ribofuranosyl) -4-amino-5- (carbaldehyde oxime) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-diphospho-β-D-ribofuranosyl) -4-amino-5- (carbaldehyde oxime) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-triphospho-β-D-ribofuranosyl) -4-amino-5- (carbaldehyde oxime) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (diisopropoxymethyl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-phospho-β-D-ribofuranosyl) -4-amino-5- (diisopropoxymethyl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-diphospho-β-D-ribofuranosyl) -4-amino-5- (diisopropoxymethyl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-triphospho-β-D-ribofuranosyl) -4-amino-5- (diisopropoxymethyl) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (boronic acid) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-phospho-β-D-ribofuranosyl) -4-amino-5- (boronic acid) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-diphospho-β-D-ribofuranosyl) -4-amino-5- (boronic acid) -pyrrolo [2,3-d] pyrimidine;
7- (2′-C-methyl-5′-triphospho-β-D-ribofuranosyl) -4-amino-5- (boronic acid) -pyrrolo [2,3-d] pyrimidine;
As well as pharmaceutically acceptable salts or partial salts thereof.   7- (2′-C-Methyl-β-D-ribofuranosyl) -4-amino-5- [2- (trimethylsilyl) -ethyn-1-yl) -pyrrolo [2,3-d] pyrimidine or a pharmaceutical thereof Or a partial salt acceptable for   7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5-[(2-pyrid-2-yl) ethyn-1-yl] -pyrrolo [2,3-d] pyrimidine or A pharmaceutically acceptable salt or partial salt thereof.   7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- [2- (pyrid-4-yl) ethyn-1-yl] -pyrrolo [2,3-d] pyrimidine or A pharmaceutically acceptable salt or partial salt thereof.   7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- [2- (4-methoxyphenyl) ethyn-1-yl] -pyrrolo [2,3-d] pyrimidine or its Pharmaceutically acceptable salt or partial salt.   7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (2-carboxamidoethyn-1-yl) -pyrrolo [2,3-d] pyrimidine or a pharmaceutically acceptable salt thereof Salt or partial salt.   7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- [3,3-diethoxypropargyl) eth-1-yl] -pyrrolo [2,3-d] pyrimidine or its Pharmaceutically acceptable salt or partial salt.   7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5-[(N, N-dimethyl-2-carboxylamido) ethyn-1-yl] -pyrrolo [2,3-d Pyrimidine or a pharmaceutically acceptable salt or partial salt thereof.   7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5-[(N-amino-2-carboxylamido) ethyn-1-yl] -pyrrolo [2,3-d] pyrimidine Or a pharmaceutically acceptable salt or partial salt thereof.   7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (2-carboxyethin-1-yl) -pyrrolo [2,3-d] pyrimidine or a pharmaceutically acceptable salt thereof Salt or partial salt.   7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5-[(ethyl 2-carboxyl) ethyn-1-yl] -pyrrolo [2,3-d] pyrimidine or a pharmaceutical thereof Or a partial salt acceptable for   7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5-[(methyl-2-carboxyl) ethyn-1-yl] -pyrrolo [2,3-d] pyrimidine or a pharmaceutical thereof Or a partial salt acceptable for   7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (2-phenylethyn-1-yl) -pyrrolo [2,3-d] pyrimidine or a pharmaceutically acceptable salt thereof Salt or partial salt.   7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (2- (4-fluorophenyl) ethyn-1-yl) -pyrrolo [2,3-d] pyrimidine or its Pharmaceutically acceptable salt or partial salt.   7- (2'-C-methyl-β-D-ribofuranosyl) -4-amino-5- (2- (4-methylphenyl) ethyn-1-yl) -pyrrolo [2,3-d] pyrimidine or its Pharmaceutically acceptable salt or partial salt.   7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (ethen-1-yl) -pyrrolo [2,3-d] pyrimidine or a pharmaceutically acceptable salt thereof Partial salt.   7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (2-cis-methoxy-ethen-1-yl) -pyrrolo [2,3-d] pyrimidine or a pharmaceutical thereof Or a partial salt acceptable for   7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (formyl) -pyrrolo [2,3-d] pyrimidine or a pharmaceutically acceptable salt or partial salt thereof.   7- (2′-methyl-β-D-ribofuranosyl) -4-amino-5- (hydrazono) -pyrrolo [2,3-d] pyrimidine or a pharmaceutically acceptable salt or partial salt thereof.   7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (carbaldehyde oxime) -pyrrolo [2,3-d] pyrimidine or a pharmaceutically acceptable salt or partial salt thereof .   7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (diisopropoxymethyl) -pyrrolo [2,3-d] pyrimidine or a pharmaceutically acceptable salt or moiety thereof salt.   7- (2′-C-methyl-β-D-ribofuranosyl) -4-amino-5- (boronic acid) -pyrrolo [2,3-d] pyrimidine or a pharmaceutically acceptable salt or partial salt thereof.   45. A pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound according to any one of claims 1 to 11 or 23 to 44 or a mixture of a plurality of such compounds. .   In mammals, a method of treating a viral infection mediated at least in part by a virus of the Flaviviridae family, wherein the mammal has been diagnosed with a viral infection or has a high risk of developing a viral infection 48. A method comprising administering a pharmaceutical composition according to claim 47.   48. The method of claim 46, wherein the virus is hepatitis C virus.   48. The method of claim 47, in combination with administration of a therapeutically effective amount of one or more agents active against HCV.   The active agent is ribavirin, levovirin, viramidine, thymosin alpha-1, inhibitor of NS3 serine protease, and inhibitor of inosine monophosphate dehydrogenase, interferon-alpha, alone or in combination with ribavirin or levovirin-pegylated interferon-alpha 49. The method of claim 48, wherein   50. The method of claim 49, wherein the agent active against HCV is interferon-α, or pegylated interferon-α alone or in combination with ribavirin or levovirin.